Open access peer-reviewed chapter

Novel Therapeutic Interventions in Systemic Lupus Erythematosus

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Panagiotis Athanassiou, Lambros Athanassiou and Ifigenia Kostoglou-Athanassiou

Submitted: 10 November 2020 Reviewed: 11 March 2021 Published: 04 May 2021

DOI: 10.5772/intechopen.97168

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. It is characterized by a variable clinical course ranging from mild to fatal disease. It can affect the kidneys. The aim of treatment in SLE is the prevention of flares and the prevention of accumulation of damage to the main organs affected as well as the prevention of drug side effects. The cornerstone of SLE treatment is hydroxychloroquine. Corticosteroids are used both as induction treatment in disease flares as well as in small doses as maintenance treatment. Immunosuppressants, such as azathioprine, methotrexate and mycophenolate mofetil are used as steroid sparing agents. Calcineurin inhibitors, namely tacrolimus and cyclosporin A may also be used as immunosuppressants and steroid sparing agents. Pulse methylprednisolone, along with mycophenolate mofetil and cyclophosphamide are used as induction treatment in lupus nephritis. Rituximab, an anti-CD20 biologic agent may be used in non-renal SLE. In patients insufficiently controlled with hydroxychloroquine, low dose prednisone and/or immunosuppressive agents, belimumab may be used with beneficial effects in non-renal disease and lupus nephritis.


  • systemic lupus erythematosus
  • treatment
  • hydroxychloroquine
  • corticosteroids
  • mycophenolate mofetil
  • rituximab
  • belimumab

1. Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting many organ systems. It has a variable course, ranging from a mild course to severe fatal disease. It affects mainly women in the reproductive age. Women of African or Asian origin suffer frequently and present with more severe disease. The treatment of SLE is in the focus of scientific interest as new immune modulating agents have entered the management of the disease.

The therapeutic management of the disease depends mainly on antimalarial agents, namely hydroxychloroquine, corticosteroids, immunosuppressive agents and biologic drugs (Figures 1 and 2). The use of hydroxychloroquine is established in SLE. Similarly, the use of corticosteroids has been in the mainstream of lupus treatment for many years. Their use is hindered by their adverse effects, which may occur even with small doses. Immunosuppressive agents such as azathioprine and methotrexate have been used as steroid sparing agents. The use of mycophenolate mofetil (MMF) is also in the mainstream treatment of severe SLE cases or lupus nephritis. Rituximab, an antiCD20 antibody targeting B lymphocytes has also been 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 non-renal 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 supplementary drugs will be reviewed.

Figure 1.

Agents involved in systemic lupus erythematosus treatment.

Figure 2.

Agents contributing to the treatment of lupus nephritis.


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 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, 35, 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.

2.3 Immunosuppressants

2.3.1 Azathioprine

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

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

2.3.3 Mycophenolate mofetil

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, 58, 59, 60, 61]. MMF is effective in non-renal lupus as well. In a systematic review of 20 case series and open-label 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, 63, 64]. By contrast, MMF appears to be more effective in preventing renal flares in high-risk populations such as African Americans [65].

2.3.4 Cyclophosphamide

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.

2.3.5 Calcineurin inhibitors

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 a complex with cyclophilin to block the phosphatase activity of calcineurin. Thus, it decreases the production of inflammatory cytokines by T lymphocytes [75]. Tacrolimus is preferentially used for lupus nephritis as it exhibits fewer side effects and is characterized by better long-term outcome [76]. Tacrolimus is a macrolide antibiotic with immunosuppressive properties. It has a mode of action similar to that of cyclosporin A, although the two drugs are structurally unrelated. It exerts its effects principally through impairment of gene expression in target cells [77]. Tacrolimus bonds to an immunophilin and this complex inhibits calcineurin phosphatase. Tacrolimus inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. It also potentiates the actions of glucocorticoids. It may enhance expression of the transforming growth factor beta-1 gene [78]. T cell proliferation, especially type 1 T helper cell, in response to ligation of the T cell receptor is inhibited by tacrolimus. Tacrolimus has been successfully applied in combination with low-dose MMF and corticosteroids as induction therapy in lupus nephritis [76, 79, 80]. Tacrolimus (0.075 mg/kg/day) has been used in refractory lupus nephritis with good results [81], however severe drug adverse events were observed, such as a high rate of infections and diabetic ketoacidosis. Cyclosporin A (2.6-3.7 mg/kg/day) has also been used in refractory lupus nephritis with good results, however drug adverse events such as tremor and hypertension have been noted [81]. Voclosporin, a novel calcineurin inhibitor is now used in lupus nephritis and is showing promising results [82].

2.3.6 Plasmapheresis

Plasmapheresis has been used successfully in refractory cases of neuropsychiatric lupus [83]. Plasmapheresis has also been applied in pregnant women with active lupus or antiphospholipid syndrome or in cases of lupus nephritis [84]. Immunoadsorption, is replacing plasmapheresis and appears to have good results [84].

2.3.7 Intravenous immunoglobulin

Therapeutic intravenous immunoglobulin (IV IG) mostly consists of human polyspecific immunoglobulin G. IV IG has been used in patients with systemic lupus erythematosus and was shown to reduce the activity of the disease [85]. IV IG may be used in cases of refractory neuropsychiatric lupus [83] and in lupus myocarditis [86].

2.4 Biologics

Biologic drugs currently incorporated in SLE treatment are rituximab [87, 88, 89] and belimumab [90, 91, 92, 93] (Figure 1). The sequential use of rituximab and belimumab is also under investigation [94, 95]. Other biologic agents targeting the B lymphocyte have also been applied [96]. Various biologic drugs have been used in treatment regimens for SLE patients with poor response or side effects to standard treatment [97]. The original goal of biologics was to induce disease remission and establish self-tolerance [98, 99]. This goal has not been achieved. It may be that the heterogeneity of disease mechanisms inherent in SLE may guide the introduction of cell- and cytokine- or pathway specific therapies which will be effective in various subgroups of SLE patients [97].

2.4.1 Rituximab

Rituximab is a humanized anti-CD20 monoclonal antibody used for B cell depletion therapy. Rituximab can induce killing of CD20+ cells via various mechanisms. The effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity [100]. Targeting the B cell has been proposed by many research studies in SLE [101]. Results from various registries have shown a favorable benefit-risk ratio in treatment refractory SLE [102, 103]. Rituximab has been shown to be safe and effective in the treatment of non-renal SLE [103]. Namely, it decreases disease activity, immunologic parameters and has a steroid-sparing effect. It can be recommended for organ-specific manifestations, such as arthritis and thrombocytopenia. Rituximab has been shown to be effective for certain refractory SLE patients, in particular refractory neuropsychiatric SLE [104]. Thus, it can be administered in this patient group. The therapeutic effect of rituximab has been compared with that of MMF and with that of cyclophosphamide in a trial of 54 lupus nephritis patients and was shown to be equally effective [105]. B cell depletion is observed but it is not complete, because early B cells and plasma cells do not express CD20 [106]. Normalization of B cell subsets has been observed in rituximab-treated SLE patients [101]. In the initial introduction of rituximab, it was suggested that complete B cell depletion might confer a better outcome for SLE [101]. However, SLE flares were observed after repeated rituximab infusions. These flares were thought to be a result of elevated circulating CD257 (BLyS) levels and high anti-dsDNA levels [107, 108]. Thus, it was proposed that B cell depletion with rituximab induced a surge in CD257 levels that may have exacerbated disease in some SLE patients [106]. In these individuals, rituximab depletion was followed by rapid peripheral B cell reconstitution, with increased circulating plasmablasts. It has been suggested that these plasmablasts might stimulate autoreactive T helper cells, which promote autoantibody production and may drive a positive feedback loop promoting disease activity [106]. Consequently, rituximab is considered in lupus nephritis only after cyclophosphamide and MMF have failed or in relapses [109]. Despite that, an analysis of the LUNAR study showed complete response with rituximab in cases of lupus nephritis [110].

2.4.2 Belimumab

Belimumab, the anti-CD257 monoclonal antibody, acts as a soluble CD257 antagonist and was the first drug approved in more than 50 years by the FDA for SLE [111, 112, 113, 114, 115, 116, 117, 118]. The recognition of B cells as central in the pathogenesis of SLE led to the development of drugs that block B cells, including antibodies to B-cell surface antigens, B-cell tolerogens, blockers of co-stimulatory molecules and inhibitors of cytokines with direct effect on B cells [119]. The BAFF/APRIL axis has been thoroughly investigated as these cytokines are vital to B-cell maturation and survival [115, 120, 121]. Belimumab is an anti-BAFF antibody. Belimumab should be considered in extrarenal lupus in patients with inadequate response to hydrochloroquine and corticosteroids and immunosuppressive drugs [122]. Patients with cutaneous and musculoskeletal manifestations are expected to respond better. Belimumab was tested in a study in which it was administered in lupus patients after rituximab [123]. The effects of belimumab on proteinuria and neuropsychiatric SLE were examined in a recent study. It was found that belimumab decreased proteinuria and improved neuropsychiatric symptoms in neuropsychiatric SLE [124]. The US Food and Drug Administration (FDA) has expanded the indication for belimumab to adults with active lupus nephritis who are receiving standard therapy. The expanded indication for belimumab for patients with LN is based on findings from the BLISS-LN phase 3 trial. In this randomized placebo controlled clinical trial on the effect of belimumab on lupus nephritis it was shown that belimumab led more patients to a primary efficacy renal response than placebo and also led to a complete renal response more patients than the placebo [125]. The risk of a renal related event or death was lower among patients receiving belimumab.

2.4.3 Obinutuzumab

Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 antibody [126]. In vitro studies have shown that obinutuzumab may induce superior B cell cytotoxicity as compared to rituximab in patients with SLE [126]. Obinutuzumab is considered an alternative B-cell depleting agent for the treatment of SLE [127]. It has been suggested that SLE patients with secondary non-response to rituximab should be preferentially switched to another B-cell depleting agent instead of belimumab [128].

2.4.4 Ofatumumab

Ofatumumab is a fully human anti-CD20 monoclonal antibody [129]. It induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in CD20-expressing B lymphocytes. Ofatumumab is highly potent in lysing B cells, as this appears to stem from its binding site on the short extracellular loop of the target CD20 protein and its slow release from the target molecule. Ofatumumab has been successfully applied in a patient with SLE and hypocomplementemia in combination with fresh frozen plasma [130]. Ofatumumab, has been used as B cell depleting therapy in SLE patients who developed severe infusion reactions to rituximab [131]. The agent was well tolerated and may be a safe and effective alternative to rituximab for B cell depletion treatment in SLE.

2.4.5 Epratuzumab

Epratuzumab is a humanized monoclonal antibody [132]. It targets CD22 on B cells and acts as B-cell modulating treatment through inhibition of B-cell receptor signaling. It has been applied in SLE [133] and found to be effective in SLE patients with Sjogren’s syndrome [134].

2.4.6 Sifalimumab

Interferons (IFNs) are a family of potent immunostimulatory cytokines that are broadly divided into three subtypes, type I, type II and type III [135]. Of all the type I IFNs, IFNα is the most abundant and is well characterized. The role of interferons in autoimmunity, especially SLE is discussed [136]. Sifalimumab is a fully human monoclonal antibody against multiple IFN-α subtypes and has shown promise in a phase IIb clinical trial in SLE [137].

2.4.7 Rigerimod

Rigerimod is a peptide which reduces the stability of MHC molecules that present antigens to T cells, thus blocking antigen presentation to autoreactive T cells thereby blocking B cell maturation. It has been tested in SLE patients with encouraging results [138].

2.5 Supplementary therapeutic modalities

Recently efforts have been made to incorporate adjunct therapeutic agents in the treatment of SLE, so, as to reduce the toxicity of traditional drugs. Prasterone and vitamin D are two immunomodulatory agents, which have been applied in the treatment of SLE as supplements, in order to control disease activity and reduce the use of corticosteroids. Prasterone is a synthetic form of the hormone dehydroepiandrosterone [139]. Its use led SLE patients to better tolerate the tapering of corticosteroids [140] and stabilized disease activity in some patients [141]. Vitamin D has immunomodulatory properties, namely it decreases inflammatory cytokines and down regulates the renin-angiotensin system [142, 143]. It may lead to the improvement of disease activity in SLE, as shown by some but not all studies [144, 145, 146].


3. Therapeutic strategies for the management of SLE

In 2014 a panel of experts introduced the treating-to-target approach in the management of SLE [147]. In 2019 an update of the EULAR recommendations for the management of SLE was published [148]. These recommendations are based both on evidence as well as on expert opinion. According to these recommendations, hydroxychloroquine should be administered to all lupus patients at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance therapy glucocorticoids should be minimized to less than 7.5 mg/day and withdrawn if possible. Initiation of immunomodulatory agents can aid in tapering or withdrawal of corticosteroids. In active or flaring extra-renal disease belimumab should be considered. Rituximab is an option for organ-threatening refractory disease. Various approaches for the treatment of SLE are currently under investigation. These include various methods to target interferon I, such as the use of anifrolumab, a human monoclonal antidoy to type I interferon receptor subunit 1 [149, 150], and to inhibit T cell co-stimulation [151]. Baricitinib, an oral selective Janus kinase1 and Janus kinase 2 inhibitor is an oral treatment, which was tested in SLE patients with favorable results [152].


4. Conclusion

Hydroxychloroquine and prednisone remain standard of care treatment for SLE. When flares occur the introduction of immunosuppressive agents and/or biologic drugs improves disease activity and disease outcome in SLE. Nowadays, the introduction of biologic agents, such as rituximab and belimumab have revolutionized the treatment of SLE and have opened new therapeutic horizons in all the spectrum of lupus disease.


  1. 1. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. Apr 2012;42(2):145-53. doi:10.1007/s12016-010-8243-x
  2. 2. Hu C, Lu L, Wan JP, Wen C. The Pharmacological Mechanisms and Therapeutic Activities of Hydroxychloroquine in Rheumatic and Related Diseases. Curr Med Chem. 2017;24(20):2241-2249. doi:10.2174/0929867324666170316115938
  3. 3. Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. Jul 1997;36(7):799-805. doi:10.1093/rheumatology/36.7.799
  4. 4. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. Oct 2015;23(5):231-69. doi:10.1007/s10787-015-0239-y
  5. 5. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401-9. doi:10.1177/s0961203307078579
  6. 6. Fischer-Betz R, Schneider M. [Antimalarials. A treatment option for every lupus patient!?]. Z Rheumatol. Sep 2009;68(7):584, 586-90. Antimalariamittel: Therapieoption für jeden Lupus-Patienten?! doi:10.1007/s00393-008-0412-4
  7. 7. Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. Oct 1993;23(2 Suppl 1):82-91. doi:10.1016/s0049-0172(10)80012-5
  8. 8. Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus. Jun 1996;5 Suppl 1:S4-10
  9. 9. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. Mar 2020;16(3):155-166. doi:10.1038/s41584-020-0372-x
  10. 10. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. Jan 2010;69(1):20-8. doi:10.1136/ard.2008.101766
  11. 11. Floris A, Piga M, Mangoni AA, Bortoluzzi A, Erre GL, Cauli A. Protective Effects of Hydroxychloroquine against Accelerated Atherosclerosis in Systemic Lupus Erythematosus. Mediators Inflamm. 2018;2018:3424136. doi:10.1155/2018/3424136
  12. 12. Penn SK, Kao AH, Schott LL, et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol. Jun 2010;37(6):1136-42. doi:10.3899/jrheum.090994
  13. 13. Ruiz-Irastorza G, Khamashta MA. Hydroxychloroquine: the cornerstone of lupus therapy. Lupus. 2008:271-3. vol. 4
  14. 14. Babary H, Liu X, Ayatollahi Y, et al. Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Int J Rheum Dis. Jan 2018;21(1):84-92. doi:10.1111/1756-185x.13159
  15. 15. Qiao X, Zhou ZC, Niu R, et al. Hydroxychloroquine Improves Obesity-Associated Insulin Resistance and Hepatic Steatosis by Regulating Lipid Metabolism. Front Pharmacol. 2019;10:855. doi:10.3389/fphar.2019.00855
  16. 16. Morris SJ, Wasko MC, Antohe JL, et al. Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res (Hoboken). Apr 2011;63(4):530-4. doi:10.1002/acr.20393
  17. 17. Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep. Feb 2011;13(1):77-80. doi:10.1007/s11926-010-0141-y
  18. 18. Pareek A, Chandurkar N, Thomas N, et al. Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone. Curr Med Res Opin. Jul 2014;30(7):1257-66. doi:10.1185/03007995.2014.909393
  19. 19. Kasturi S, Sammaritano LR. Corticosteroids in Lupus. Rheum Dis Clin North Am. Feb 2016;42(1):47-62, viii. doi:10.1016/j.rdc.2015.08.007
  20. 20. Ugarte A, Danza A, Ruiz-Irastorza G. Glucocorticoids and antimalarials in systemic lupus erythematosus: an update and future directions. Curr Opin Rheumatol. Sep 2018;30(5):482-489. doi:10.1097/bor.0000000000000527
  21. 21. Vandewalle J, Luypaert A, De Bosscher K, Libert C. Therapeutic Mechanisms of Glucocorticoids. Trends Endocrinol Metab. Jan 2018;29(1):42-54. doi:10.1016/j.tem.2017.10.010
  22. 22. Dasgupta S. Therapeutic Interventions of Tissue Specific Autoimmune Onset in Systemic Lupus Erythematosus. Mini Rev Med Chem. 2017;17(15):1418-1424. doi:10.2174/1389557516666160611020838
  23. 23. Strehl C, Ehlers L, Gaber T, Buttgereit F. Glucocorticoids-All-Rounders Tackling the Versatile Players of the Immune System. Front Immunol. 2019;10:1744. doi:10.3389/fimmu.2019.01744
  24. 24. Newton R, Holden NS. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol Pharmacol. Oct 2007;72(4):799-809. doi:10.1124/mol.107.038794
  25. 25. Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus. Oct 2013;22(12):1286-94. doi:10.1177/0961203313493032
  26. 26. Yates DJ, Mon SY, Oh Y, et al. Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus. Lupus Sci Med. Sep 2020;7(1)doi:10.1136/lupus-2020-000390
  27. 27. Ruiz-Arruza I, Ugarte A, Cabezas-Rodriguez I, Medina JA, Moran MA, Ruiz-Irastorza G. Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus. Rheumatology (Oxford). Aug 2014;53(8):1470-6. doi:10.1093/rheumatology/keu148
  28. 28. Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum. Aug 2000;43(8):1801-8. doi:10.1002/1529-0131(200008)43:8<1801::aid-anr16>;2-o
  29. 29. Ruiz-Irastorza G, Ugarte A, Saint-Pastou Terrier C, et al. Repeated pulses of methyl-prednisolone with reduced doses of prednisone improve the outcome of class III, IV and V lupus nephritis: An observational comparative study of the Lupus-Cruces and lupus-Bordeaux cohorts. Autoimmun Rev. Aug 2017;16(8):826-832. doi:10.1016/j.autrev.2017.05.017
  30. 30. Mosca M, Neri R, Giannessi S, et al. Therapy with pulse methylprednisolone and short course pulse cyclophosphamide for diffuse proliferative glomerulonephritis. Lupus. 2001;10(4):253-7. doi:10.1191/096120301680416931
  31. 31. Badsha H, Edwards CJ. Intravenous pulses of methylprednisolone for systemic lupus erythematosus. Semin Arthritis Rheum. Jun 2003;32(6):370-7. doi:10.1053/sarh.2002.50003
  32. 32. Badsha H, Kong KO, Lian TY, Chan SP, Edwards CJ, Chng HH. Low-dose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications. Lupus. 2002;11(8):508-13. doi:10.1191/0961203302lu243oa
  33. 33. Roccatello D, Sciascia S, Rossi D, et al. Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant. Dec 2011;26(12):3987-92. doi:10.1093/ndt/gfr109
  34. 34. Ruiz-Arruza I, Barbosa C, Ugarte A, Ruiz-Irastorza G. Comparison of high versus low-medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis. Autoimmun Rev. Oct 2015;14(10):875-9. doi:10.1016/j.autrev.2015.05.011
  35. 35. Mathian A, Pha M, Haroche J, et al. Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial. Ann Rheum Dis. Mar 2020;79(3):339-346. doi:10.1136/annrheumdis-2019-216303
  36. 36. van Vollenhoven R, Voskuyl A, Bertsias G, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. Mar 2017;76(3):554-561. doi:10.1136/annrheumdis-2016-209519
  37. 37. Abu-Shakra M, Shoenfeld Y. Azathioprine therapy for patients with systemic lupus erythematosus. Lupus. 2001;10(3):152-3. doi:10.1191/096120301676669495
  38. 38. Aarbakke J, Janka-Schaub G, Elion GB. Thiopurine biology and pharmacology. Trends Pharmacol Sci. 1997:3-7. vol. 1
  39. 39. Patel AA, Swerlick RA, McCall CO. Azathioprine in dermatology: the past, the present, and the future. J Am Acad Dermatol. Sep 2006;55(3):369-89. doi:10.1016/j.jaad.2005.07.059
  40. 40. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest. Apr 2003;111(8):1122-4. doi:10.1172/jci18384
  41. 41. Saavedra M, Sánchez A, Morales S, Ángeles U, Jara LJ. Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor fetal outcome. Clin Rheumatol. Jul 2015;34(7):1211-6. doi:10.1007/s10067-015-2987-x
  42. 42. Jaryal A, Vikrant S. Current status of lupus nephritis. Indian J Med Res. Feb 2017;145(2):167-178. doi:10.4103/ijmr.IJMR_163_16
  43. 43. Fortin PR, Abrahamowicz M, Ferland D, Lacaille D, Smith CD, Zummer M. Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. Dec 15 2008;59(12):1796-804. doi:10.1002/art.24068
  44. 44. Muangchan C, van Vollenhoven RF, Bernatsky SR, et al. Treatment Algorithms in Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). Sep 2015;67(9):1237-1245. doi:10.1002/acr.22589
  45. 45. Chan ES, Cronstein BN. Mechanisms of action of methotrexate. Bull Hosp Jt Dis (2013). 2013;71 Suppl 1:S5-8
  46. 46. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. Mar 2020;16(3):145-154. doi:10.1038/s41584-020-0373-9
  47. 47. Bedoui Y, Guillot X, Sélambarom J, et al. Methotrexate an Old Drug with New Tricks. Int J Mol Sci. Oct 10 2019;20(20)doi:10.3390/ijms20205023
  48. 48. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am. Nov 1997;23(4):739-55. doi:10.1016/s0889-857x(05)70358-6
  49. 49. Chan ES, Cronstein BN. Methotrexate--how does it really work? Nat Rev Rheumatol. 2010:175-8
  50. 50. Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis. Feb 2008;67(2):195-205. doi:10.1136/ard.2007.070367
  51. 51. Vroom F, de Walle HE, van de Laar MA, Brouwers JR, de Jong-van den Berg LT. Disease-modifying antirheumatic drugs in pregnancy: current status and implications for the future. Drug Saf. 2006;29(10):845-63. doi:10.2165/00002018-200629100-00003
  52. 52. Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol. Sep 2007;2(5):968-75. doi:10.2215/cjn.01200307
  53. 53. Pisoni CN, Karim Y, Cuadrado MJ. Mycophenolate mofetil and systemic lupus erythematosus: an overview. Lupus. 2005;14 Suppl 1:s9-11. doi:10.1191/0961203305lu2111oa
  54. 54. Joo YB, Kang YM, Kim HA, et al. Outcome and predictors of renal survival in patients with lupus nephritis: Comparison between cyclophosphamide and mycophenolate mofetil. Int J Rheum Dis. May 2018;21(5):1031-1039. doi:10.1111/1756-185x.13274
  55. 55. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14 Suppl 1:s2-8. doi:10.1191/0961203305lu2109oa
  56. 56. Fassbinder T, Saunders U, Mickholz E, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther. Apr 3 2015;17(1):92. doi:10.1186/s13075-015-0603-8
  57. 57. Morris HK, Canetta PA, Appel GB. Impact of the ALMS and MAINTAIN trials on the management of lupus nephritis. Nephrol Dial Transplant. Jun 2013;28(6):1371-6. doi:10.1093/ndt/gfs447
  58. 58. Sinclair A, Appel G, Dooley MA, et al. Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS). Lupus. 2007;16(12):972-80. doi:10.1177/0961203307084712
  59. 59. Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. Dec 2010;69(12):2083-9. doi:10.1136/ard.2010.131995
  60. 60. Stoenoiu MS, Aydin S, Tektonidou M, et al. Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial. Nephrol Dial Transplant. May 2012;27(5):1924-30. doi:10.1093/ndt/gfr553
  61. 61. Ginzler EM, Wofsy D, Isenberg D, Gordon C, Lisk L, Dooley MA. Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective, randomized, open-label, parallel-group clinical trial. Arthritis Rheum. Jan 2010;62(1):211-21. doi:10.1002/art.25052
  62. 62. Mok CC. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol. Sep-Oct 2007;36(5):329-37. doi:10.1080/03009740701607042
  63. 63. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. May 2009;20(5):1103-12. doi:10.1681/asn.2008101028
  64. 64. Houssiau FA, Vasconcelos C, D'Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. Jan 2010;69(1):61-4. doi:10.1136/ard.2008.102533
  65. 65. Yap DY, Chan TM. Lupus Nephritis in Asia: Clinical Features and Management. Kidney Dis (Basel). Sep 2015;1(2):100-9. doi:10.1159/000430458
  66. 66. Hurd ER, Ziff M. The mechanism of action of cyclophosphamide on the nephritis of (NZB x NZW)F1 hybrid mice. Clin Exp Immunol. Jul 1977;29(1):132-9
  67. 67. Amano H, Morimoto S, Kaneko H, Tokano Y, Takasaki Y, Hashimoto H. Effect of intravenous cyclophosphamide in systemic lupus erythematosus: relation to lymphocyte subsets and activation markers. Lupus. 2000;9(1):26-32. doi:10.1177/096120330000900106
  68. 68. Koo HS, Kim YC, Lee SW, et al. The effects of cyclophosphamide and mycophenolate on end-stage renal disease and death of lupus nephritis. Lupus. Nov 2011;20(13):1442-9. doi:10.1177/0961203311416034
  69. 69. Martin F, Lauwerys B, Lefèbvre C, Devogelaer JP, Houssiau FA. Side-effects of intravenous cyclophosphamide pulse therapy. Lupus. 1997;6(3):254-7. doi:10.1177/096120339700600307
  70. 70. Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. Aug 2002;46(8):2121-31. doi:10.1002/art.10461
  71. 71. Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. Sep 2008;14(9):931-8. doi:10.1038/nm.1857
  72. 72. Pego-Reigosa JM, Cobo-Ibáñez T, Calvo-Alén J, et al. Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: a systematic review. Arthritis Care Res (Hoboken). Nov 2013;65(11):1775-85. doi:10.1002/acr.22035
  73. 73. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. Apr 1992;13(4):136-42. doi:10.1016/0167-5699(92)90111-j
  74. 74. Russell G, Graveley R, Seid J, al-Humidan AK, Skjodt H. Mechanisms of action of cyclosporine and effects on connective tissues. Semin Arthritis Rheum. Jun 1992;21(6 Suppl 3):16-22. doi:10.1016/0049-0172(92)90009-3
  75. 75. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. May 2000;47(2-3):119-25. doi:10.1016/s0162-3109(00)00192-2
  76. 76. Mok CC. Towards new avenues in the management of lupus glomerulonephritis. Nat Rev Rheumatol. Apr 2016;12(4):221-34. doi:10.1038/nrrheum.2015.174
  77. 77. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. Dec 1995;17(6):584-91. doi:10.1097/00007691-199512000-00007
  78. 78. Yoon KH. Efficacy and cytokine modulating effects of tacrolimus in systemic lupus erythematosus: a review. J Biomed Biotechnol. 2010;2010:686480. doi:10.1155/2010/686480
  79. 79. Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol. Oct 2008;19(10):2001-10. doi:10.1681/asn.2007121272
  80. 80. Liu Z, Zhang H, Xing C, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. Jan 6 2015;162(1):18-26. doi:10.7326/m14-1030
  81. 81. Kronbichler A, Brezina B, Gauckler P, Quintana LF, Jayne DRW. Refractory lupus nephritis: When, why and how to treat. Autoimmun Rev. May 2019;18(5):510-518. doi:10.1016/j.autrev.2019.03.004
  82. 82. Rovin BH, Solomons N, Pendergraft WF, 3rd, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. Jan 2019;95(1):219-231. doi:10.1016/j.kint.2018.08.025
  83. 83. Magro-Checa C, Zirkzee EJ, Huizinga TW, Steup-Beekman GM. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs. Mar 2016;76(4):459-83. doi:10.1007/s40265-015-0534-3
  84. 84. Kronbichler A, Brezina B, Quintana LF, Jayne DR. Efficacy of plasma exchange and immunoadsorption in systemic lupus erythematosus and antiphospholipid syndrome: A systematic review. Autoimmun Rev. Jan 2016;15(1):38-49. doi:10.1016/j.autrev.2015.08.010
  85. 85. Sakthiswary R, D'Cruz D. Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore). Oct 2014;93(16):e86. doi:10.1097/md.0000000000000086
  86. 86. Suri V, Varma S, Joshi K, Malhotra P, Kumari S, Jain S. Lupus myocarditis: marked improvement in cardiac function after intravenous immunoglobulin therapy. Rheumatol Int. Sep 2010;30(11):1503-5. doi:10.1007/s00296-009-1098-x
  87. 87. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. Jan 2010;62(1):222-33. doi:10.1002/art.27233
  88. 88. Pirone C, Mendoza-Pinto C, van der Windt DA, Parker B, M OS, Bruce IN. Predictive and prognostic factors influencing outcomes of rituximab therapy in systemic lupus erythematosus (SLE): A systematic review. Semin Arthritis Rheum. Dec 2017;47(3):384-396. doi:10.1016/j.semarthrit.2017.04.010
  89. 89. Iwata S, Saito K, Hirata S, et al. Efficacy and safety of anti-CD20 antibody rituximab for patients with refractory systemic lupus erythematosus. Lupus. Apr 2018;27(5):802-811. doi:10.1177/0961203317749047
  90. 90. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. Feb 26 2011;377(9767):721-31. doi:10.1016/s0140-6736(10)61354-2
  91. 91. Blair HA, Duggan ST. Belimumab: A Review in Systemic Lupus Erythematosus. Drugs. Mar 2018;78(3):355-366. doi:10.1007/s40265-018-0872-z
  92. 92. Poh YJ, Baptista B, D'Cruz DP. Subcutaneous and intravenous belimumab in the treatment of systemic lupus erythematosus: a review of data on subcutaneous and intravenous administration. Expert Rev Clin Immunol. Oct 2017;13(10):925-938. doi:10.1080/1744666x.2017.1371592
  93. 93. Wallace DJ, Ginzler EM, Merrill JT, et al. Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol. Jul 2019;71(7):1125-1134. doi:10.1002/art.40861
  94. 94. Kraaij T, Kamerling SWA, de Rooij ENM, et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun. Jul 2018;91:45-54. doi:10.1016/j.jaut.2018.03.003
  95. 95. Gualtierotti R, Borghi MO, Gerosa M, et al. Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. Clin Exp Rheumatol. Jul-Aug 2018;36(4):643-647
  96. 96. Lee WS, Amengual O. B cells targeting therapy in the management of systemic lupus erythematosus. Immunol Med. Mar 2020;43(1):16-35. doi:10.1080/25785826.2019.1698929
  97. 97. Davis LS, Reimold AM. Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford). Apr 1 2017;56(suppl_1):i100-i113. doi:10.1093/rheumatology/kew417
  98. 98. Magro R. Biological therapies and their clinical impact in the treatment of systemic lupus erythematosus. Ther Adv Musculoskelet Dis. 2019;11:1759720x19874309. doi:10.1177/1759720x19874309
  99. 99. Samotij D, Reich A. Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review. Biomed Res Int. 2019;2019:8142368. doi:10.1155/2019/8142368
  100. 100. Cerny T, Borisch B, Introna M, Johnson P, Rose AL. Mechanism of action of rituximab. Anticancer Drugs. Nov 2002;13 Suppl 2:S3-10. doi:10.1097/00001813-200211002-00002
  101. 101. Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol. Jun 2010;6(6):326-37. doi:10.1038/nrrheum.2010.68
  102. 102. Witt M, Grunke M, Proft F, et al. Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID). Lupus. Oct 2013;22(11):1142-9. doi:10.1177/0961203313503912
  103. 103. Cobo-Ibáñez T, Loza-Santamaría E, Pego-Reigosa JM, et al. Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: a systematic review. Semin Arthritis Rheum. Oct 2014;44(2):175-85. doi:10.1016/j.semarthrit.2014.04.002
  104. 104. Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis. Apr 2007;66(4):470-5. doi:10.1136/ard.2006.057885
  105. 105. Moroni G, Raffiotta F, Trezzi B, et al. Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology (Oxford). Sep 2014;53(9):1570-7. doi:10.1093/rheumatology/ket462
  106. 106. Ehrenstein MR, Wing C. The BAFFling effects of rituximab in lupus: danger ahead? Nat Rev Rheumatol. Jun 2016;12(6):367-72. doi:10.1038/nrrheum.2016.18
  107. 107. Lazarus MN, Turner-Stokes T, Chavele KM, Isenberg DA, Ehrenstein MR. B-cell numbers and phenotype at clinical relapse following rituximab therapy differ in SLE patients according to anti-dsDNA antibody levels. Rheumatology (Oxford). Jul 2012;51(7):1208-15. doi:10.1093/rheumatology/ker526
  108. 108. Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. Oct 2013;65(10):2672-9. doi:10.1002/art.38074
  109. 109. Díaz-Lagares C, Croca S, Sangle S, et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev. Mar 2012;11(5):357-64. doi:10.1016/j.autrev.2011.10.009
  110. 110. Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis. Clin J Am Soc Nephrol. Oct 8 2018;13(10):1502-1509. doi:10.2215/cjn.01070118
  111. 111. Stohl W. Future prospects in biologic therapy for systemic lupus erythematosus. Nat Rev Rheumatol. Dec 2013;9(12):705-20. doi:10.1038/nrrheum.2013.136
  112. 112. Morais SA, Vilas-Boas A, Isenberg DA. B-cell survival factors in autoimmune rheumatic disorders. Ther Adv Musculoskelet Dis. Aug 2015;7(4):122-51. doi:10.1177/1759720x15586782
  113. 113. Vilas-Boas A, Morais SA, Isenberg DA. Belimumab in systemic lupus erythematosus. RMD Open. 2015;1(1):e000011. doi:10.1136/rmdopen-2014-000011
  114. 114. Naradikian MS, Perate AR, Cancro MP. BAFF receptors and ligands create independent homeostatic niches for B cell subsets. Curr Opin Immunol. Jun 2015;34:126-9. doi:10.1016/j.coi.2015.03.005
  115. 115. Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. Jun 2014;10(6):365-73. doi:10.1038/nrrheum.2014.33
  116. 116. Dillon SR, Harder B, Lewis KB, et al. B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin. Arthritis Res Ther. 2010;12(2):R48. doi:10.1186/ar2959
  117. 117. Roschke V, Sosnovtseva S, Ward CD, et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J Immunol. Oct 15 2002;169(8):4314-21. doi:10.4049/jimmunol.169.8.4314
  118. 118. Stohl W. Systemic lupus erythematosus and its ABCs (APRIL/BLyS complexes). Arthritis Res Ther. 2010:111. vol. 2
  119. 119. Mok MY. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis. Feb 1 2010;13(1):3-11. doi:10.1111/j.1756-185X.2009.01458.x
  120. 120. Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. Nov 20 2000;192(10):1453-66. doi:10.1084/jem.192.10.1453
  121. 121. Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol. 2003;21:231-64. doi:10.1146/annurev.immunol.21.120601.141152
  122. 122. Guerreiro Castro S, Isenberg DA. Belimumab in systemic lupus erythematosus (SLE): evidence-to-date and clinical usefulness. Ther Adv Musculoskelet Dis. Mar 2017;9(3):75-85. doi:10.1177/1759720x17690474
  123. 123. Jones A, Muller P, Dore CJ, et al. Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial. BMJ Open. Dec 16 2019;9(12):e032569. doi:10.1136/bmjopen-2019-032569
  124. 124. Plüß M, Tampe B, Niebusch N, Zeisberg M, Müller GA, Korsten P. Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus. Front Med (Lausanne). 2020;7:222. doi:10.3389/fmed.2020.00222
  125. 125. Furie R, Rovin BH, Houssiau F, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. Sep 17 2020;383(12):1117-1128. doi:10.1056/NEJMoa2001180
  126. 126. Reddy V, Klein C, Isenberg DA, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford). Jul 1 2017;56(7):1227-1237. doi:10.1093/rheumatology/kex067
  127. 127. Reddy V, Dahal LN, Cragg MS, Leandro M. Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? Drug Discov Today. Aug 2016;21(8):1330-8. doi:10.1016/j.drudis.2016.06.009
  128. 128. Hassan SU, Md Yusof MY, Emery P, Dass S, Vital EM. Biologic Sequencing in Systemic Lupus Erythematosus: After Secondary Non-response to Rituximab, Switching to Humanised Anti-CD20 Agent Is More Effective Than Belimumab. Front Med (Lausanne). 2020;7:498. doi:10.3389/fmed.2020.00498
  129. 129. Sanford M, McCormack PL. Ofatumumab. Drugs. May 28 2010;70(8):1013-9. doi:10.2165/11203850-000000000-00000
  130. 130. Speth F, Hinze C, Häfner R. Combination of ofatumumab and fresh frozen plasma in hypocomplementemic systemic lupus erythematosus: a case report. Lupus. Jul 2018;27(8):1395-1396. doi:10.1177/0961203318756289
  131. 131. Masoud S, McAdoo SP, Bedi R, Cairns TD, Lightstone L. Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab. Rheumatology (Oxford). Jul 1 2018;57(7):1156-1161. doi:10.1093/rheumatology/key042
  132. 132. Rao V, Gordon C. Evaluation of epratuzumab as a biologic therapy in systemic lupus erythematosus. Immunotherapy. 2014;6(11):1165-75. doi:10.2217/imt.14.80
  133. 133. Geh D, Gordon C. Epratuzumab for the treatment of systemic lupus erythematosus. Expert Rev Clin Immunol. Apr 2018;14(4):245-258. doi:10.1080/1744666x.2018.1450141
  134. 134. Gottenberg JE, Dörner T, Bootsma H, et al. Efficacy of Epratuzumab, an Anti-CD22 Monoclonal IgG Antibody, in Systemic Lupus Erythematosus Patients With Associated Sjögren's Syndrome: Post Hoc Analyses From the EMBODY Trials. Arthritis Rheumatol. May 2018;70(5):763-773. doi:10.1002/art.40425
  135. 135. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;32:513-45. doi:10.1146/annurev-immunol-032713-120231
  136. 136. Rönnblom L. The importance of the type I interferon system in autoimmunity. Clin Exp Rheumatol. Jul-Aug 2016;34(4 Suppl 98):21-4
  137. 137. Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. Nov 2016;75(11):1909-1916. doi:10.1136/annrheumdis-2015-208562
  138. 138. Zimmer R, Scherbarth HR, Rillo OL, Gomez-Reino JJ, Muller S. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis. Nov 2013;72(11):1830-5. doi:10.1136/annrheumdis-2012-202460
  139. 139. Rutkowski K, Sowa P, Rutkowska-Talipska J, Kuryliszyn-Moskal A, Rutkowski R. Dehydroepiandrosterone (DHEA): hypes and hopes. Drugs. Jul 2014;74(11):1195-207. doi:10.1007/s40265-014-0259-8
  140. 140. Petri MA, Lahita RG, Van Vollenhoven RF, et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. Jul 2002;46(7):1820-9. doi:10.1002/art.10364
  141. 141. Sánchez-Guerrero J, Fragoso-Loyo HE, Neuwelt CM, et al. Effects of prasterone on bone mineral density in women with active systemic lupus erythematosus receiving chronic glucocorticoid therapy. J Rheumatol. Aug 2008;35(8):1567-75
  142. 142. Targher G, Pichiri I, Lippi G. Vitamin D, thrombosis, and hemostasis: more than skin deep. Semin Thromb Hemost. Feb 2012;38(1):114-24. doi:10.1055/s-0031-1300957
  143. 143. Brøndum-Jacobsen P, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. 25-Hydroxyvitamin D concentrations and risk of venous thromboembolism in the general population with 18,791 participants. J Thromb Haemost. Mar 2013;11(3):423-31. doi:10.1111/jth.12118
  144. 144. Petri M, Bello KJ, Fang H, Magder LS. Vitamin D in systemic lupus erythematosus: modest association with disease activity and the urine protein-to-creatinine ratio. Arthritis Rheum. Jul 2013;65(7):1865-71. doi:10.1002/art.37953
  145. 145. Andreoli L, Dall’Ara F, Piantoni S, et al. A 24-month prospective study on the efficacy and safety of two different monthly regimens of vitamin D supplementation in pre-menopausal women with systemic lupus erythematosus. Lupus. Apr 2015;24(4-5):499-506. doi:10.1177/0961203314559089
  146. 146. Aranow C, Kamen DL, Dall'Era M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol. Jul 2015;67(7):1848-57. doi:10.1002/art.39108
  147. 147. van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. Jun 2014;73(6):958-67. doi:10.1136/annrheumdis-2013-205139
  148. 148. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. Jun 2019;78(6):736-745. doi:10.1136/annrheumdis-2019-215089
  149. 149. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. Feb 2017;69(2):376-386. doi:10.1002/art.39962
  150. 150. Merrill JT, Furie R, Werth VP, et al. Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus. Lupus Sci Med. 2018;5(1):e000284. doi:10.1136/lupus-2018-000284
  151. 151. Lateef A, Petri M. Biologics in the treatment of systemic lupus erythematosus. Curr Opin Rheumatol. Sep 2010;22(5):504-9. doi:10.1097/BOR.0b013e32833b475e
  152. 152. Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. Jul 21 2018;392(10143):222-231. doi:10.1016/s0140-6736(18)31363-1

Written By

Panagiotis Athanassiou, Lambros Athanassiou and Ifigenia Kostoglou-Athanassiou

Submitted: 10 November 2020 Reviewed: 11 March 2021 Published: 04 May 2021