Review

Pharmacotherapy of systemic lupus erythematosus

Lisa Francis & Andras Perl
1. 2. 3. 4. 5. 6. 7. 8. Introduction Constitutional symptoms Atherosclerosis prophylaxis Pregnancy New therapies in systemic lupus erythematosus Monitoring of drug safety and side effects in patients with SLE Conclusions Expert opinion

Division of Rheumatology, Department of Medicine, SUNY, Syracuse, NY 13210, USA

The pharmacological management of systemic lupus erythematosus (SLE) is challenging owing to its unpredictable clinical course, the variable organ system involvement and the lack of clear understanding of disease pathogenesis. The widely used corticosteroids and immunosuppressive drugs, which can control disease activity, have serious, potentially fatal, side effects. In the last decade, a better understanding of lupus pathogenesis has led to the development of biological agents that are directed at biomarkers. However, these biologicals also exert side effects due to infections resulting from completely eliminating immune cells (e.g., B cells) or cytokine signals (e.g., interferon-) or affecting molecular targets outside the immune system (CD40L on platelets). New biomarker-driven clinical trials are ongoing to evaluate the safety and efficacy of B-cell depletion, blocking of interferon signaling, inhibition of the mTOR pathway, and restoration of glutathione deficiency in lupus T cells.
Keywords: biological, biomarkers, corticosteroids, immunosuppressive drugs, systemic lupus erythematosus Expert Opin. Pharmacother. (2009) 10(9):1481-1494

1. Introduction

The management of systemic lupus erythematosus (SLE) has always been challenging because of its variable disease manifestations and unpredictable disease course. The treatment should be individualized for each patient since one treatment modality that works for one patient may not work for another. The patients should be closely monitored for exacerbations of the disease and for complications from the treatment. Clinical trials in SLE have been difficult owing to the heterogeneity of the disease and the lack of definite markers for diagnosis and monitoring of disease activity. To decide on an effective therapeutic regimen, there should be an accurate assessment of disease activity and severity. A number of scoring indices have been developed Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [1]; Systemic Lupus Activity Measure (SLAM); British Isles Lupus Assessment Group (BILAG) [2]; European Consensus Lupus Activity Measurement (ECLAM) in an attempt to monitor disease activity accurately. All SLE patients need education, counseling and support because of the complex nature of the disease and unpredictability of the disease process. At present, there are only four medications approved by the FDA for the treatment of SLE. These include: prednisone as adjunctive therapy or short-term administration (to tide the patient over an acute exacerbation) in the treatment of SLE; hydroxy chloroquine for the treatment of discoid lupus and SLE; aspirin for the arthritis and pleurisy of SLE; and triamcinolone hexacetonide for intralesional injection in discoid lupus erythematosus (Rheumatology Therapeutics: Drugs and Biologics Center for Drug Evaluation and Research) (Table 1). Research is ongoing for better treatment modalities for SLE. In this paper, we review the treatment options available for the management of lupus. The review focuses on establishing the hierarchy of the

10.1517/14656560902971003 2009 Informa UK Ltd ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted

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Table 1. FDA-approved drugs for management of systemic lupus erythematosus (sle).

Drug Prednisone Dosage 530 mg in single or divided doses 200400 mg daily 3 g daily in divided doses Intralesional injection Indication Flare-up and maintenance treatment of SLE Discoid lupus and SLE Arthritis and pleurisy Discoid lupus

Hydroxychloroquine Aspirin Triamcinolone hexacetonide

Ref: Rheumatology Therapeutics: Drugs and Biologics. Center for Drug Evaluation and Research (CDER).

signaling pathways that underlie abnormal activation of T and B cells, altered cytokine expression and antinuclear antibody production, and identifies check points that can be targeted for therapeutic intervention in SLE.
2. Constitutional symptoms

and high potency (betamethasone dipropionate, 0.05%). A randomized, placebo-controlled study of hydroxy chloroquine 400 mg daily showed significant photoprotective effects in patients with polymorphic light eruption [5]. Topical cyclosporine and pimecrolimus have been effective in treating severe SLE rash [6]. In patients with severe cutaneous lupus not responding to steroids or antimalarials, especially in patients with bullous lupus, lupus panniculitis, vasculitic lesions and oral ulcers, dapsone has been used with benefit [7]. Thalidomide has also been proven to be useful in cases of refractory cutaneous lupus. Its serious side effects including teratogenicity and peripheral neuropathy preclude its more widespread use. A negative pregnancy test must be obtained and reliable contraceptive measures should be strictly observed before starting treatment with thalidomide [8]. There have been several case reports of cutaneous SLE responding to anti-TNF therapies including infliximab and etanercept [9,10].
2.2 Musculoskeletal

Constitutional symptoms in SLE are difficult to treat. NSAIDs are usually effective in the treatment of constitutional symptoms; low-dose corticosteroids can be used if NSAIDs are not effective or if there is a contraindication to the use of NSAIDs. Consideration could be given to the use of corticosteroids in clinically stable patients who develop evidence of serologic activity [3].
2.1 Cutaneous

SLE can cause a variety of cutaneous lesions, the most characteristic of which is the butterfly rash sparing the nasolabial folds. Subacute cutaneous lupus erythematosus (SCLE) is a distinct cutaneous lesion which is non-fixed, non-scarring, exacerbating and remitting and can appear in various forms, ranging from papules, papulosquamous lesions to granuloma annulare-like lesions. SCLE may be accompanied by musculoskeletal complaints and serological abnormalities, most commonly antibody to Ro or Sjogren syndrome A antigen (SSA). Photosensitivity occurs in 75% of patients with SLE and exposure to ultraviolet B (UVB) is the most common cause. Ultraviolet A (UVA) light can also cause photosensitivity. Protection against UV light can be achieved by using protective clothing, tinted glass and sunscreens. The sun protection factor (SPF) is defined as the dose of UV radiation required to produce 1 minimal erythema dose (MED) on protected skin after application of 2 mg/cm2 of sunscreen product divided by the UV radiation required to produce 1 MED on unprotected skin [4]. Patients with cutaneous lupus should be advised to use broad-spectrum sunscreens that contain agents that block UVB and UVA with an SPF of 30 or greater [4]. Topical steroids are effective in the treatment of cutaneous lupus. Topical steroids may be low potency (hydrocortisone, 1 2.5%), medium potency (triamcinolone, 0.025 0.1%)
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Altough NSAIDs are not specifically approved by the FDA for use in SLE, they are commonly used for mild lupus activity in the joints before low-dose corticosteroids are initiated. Efficacy of hydroxychloroquine for skin and joint manifestations of SLE has been well established [11,12]. Antimalarials should be considered in new patients with lupus. The onset of action is slow, but once active it may prevent progression of mild lupus to more severe disease with major organ involvement [5]. Hydroxy chloroquine use has been associated with lower serum concentrations of cholesterol, triglycerides and low-density lipoproteins in lupus patients. The failure of treatment with antimalarial drugs often results in long-term treatment with high doses of corticosteroids. In patients who have SLE, weekly methotrexate was reported to be effective in the treatment of arthritis and skin disease [13,14]. Methotrexate can be used as a steroid sparing agent reducing further morbidity related to treatment [15]. Mycophenolate mofetil (MMF) can be used in musculoskeletal lupus or as a steroid sparing agent [16].
2.3 Glomerulonephritis

Intravenous cyclophosphamide has been the standard of care for the management of severe lupus glomerulonephritis [17-19] (Table 2), but its use has been limited by potentially severe toxic effects, which include bone marrow suppression, hemorrhagic cystitis, opportunistic infections, malignant diseases and premature gonadal failure [20]. Controlled trials have shown that pulse cyclophosphamide is the treatment of choice for patients with moderate to severe proliferative nephritis [21-23]. Combining pulse cyclophosphamide with pulse methyl prednisolone increases efficacy but not toxicity. In a series of long-term studies in patients with SLE nephritis, treatment with glucocorticoids plus cyclophosphamide for more than 2 years was found to be superior to glucocorticoids plus azathioprine, and both regimes were

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Table 2. standard therapy for systemic lupus erythematosus (sle).

General Patient education Social and psychological support Close monitoring to detect complications from the disease or treatment: osteoporosis prevention for patients on steroids and postmenopausal women; avascular necrosis in patients on steroids Aggressive management of associated medical problems(e.g., hypertension, infection, hyperlipidemia) Sunscreens Topical steroids: hydrocortisone 1 2.5%; triamcinolone 0.025 0.1%; betamethasone dipropionate 0.05% Antimalarial agents (usually hydroxy chloroquine) Systemic steroids In refractory cases, consider immunosuppression (azathioprine, mycophenolate mofetil) NSAIDs Systemic steroids: prednisone 5 30 mg in single or divided doses Antimalarial agents (hydroxychloroquine is most frequently used, at 200 400 mg/day) Leflunomide 40 mg daily Steroid sparing agents (e.g., methotrexate 7.5 30 mg weekly, azathioprine 50 200 mg daily) [98] Cyclophosphamide pulse therapy 0.5 1.0 g/m2 monthly pulses for 6 months, then quarterly for up to 18 months Pulse methyl prednisolone 1 g/m2 or Oral prednisone 1 mg/kg Mycophenolate mofetil 1-2 g orally twice daily NSAIDs, steroids Hydroxychloroquine (for prevention of flare) Calcium channel blockers, prostaglandin analogs, phosphodiesterase inhibitor Bosentan Iloprost Pulse methylprednisolone High-dose corticosteroids Pulse methyl prednisolone 1 g i.v. daily for 3 days Pulse cyclophosphamide Aspirin Long term anticoagulation Catastrophic APS-plasmapheresis, rituximab Mycophenolate mofetil, rituximab

Cutaneous

Musculoskeletal Arthritis/constitutional symptoms

Renal

Cardiopulmonary Pleuritis/pericarditis Pulmonary hypertension

Pulmonary hemorrhage Neuropsychiatric

Hematologic Antiphospholipid antibody syndrome Hemolytic anemia, Thrombocytopenia

superior to glucocorticoids alone in preventing renal failure in these patients [24]. MMF has been successfully used as a substitute for cyclophosphamide in the treatment of lupus nephritis in an effort to reduce serious adverse effects from the use of cyclophosphamide. It selectively suppresses T and B lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase, an enzyme involved in de novo purine nucleotide synthesis [25]. The efficacy of MMF as induction therapy was assessed in four randomized, controlled trials, which concluded that MMF was associated with a reduced incidence of treatment failure (relative risk (RR) = 0.7) and composite end point of death or end-stage renal disease (ESRD) (RR = 0.4) compared with cyclophosphamide [20,26-28]. Maintenance therapies with MMF or azathioprine following short-term cyclophosphamide induction in a sequential regimen are efficacious and safe for

the treatment of high-risk patients with proliferative lupus nephritis [29, 111]. The Aspreva Lupus Management Study (ALMS) is a multinational Phase III study designed to compare induction treatment of proliferative lupus nephritis using pulsed intravenous cyclophosphamide 0.5 1.0 g/m2 monthly or MMF 3 g/day orally, followed by further randomization into maintenance treatment with either azathioprine or MMF 2 g/day. The induction phase of this trial has been completed. Although the remission rate was comparable between MMF and cyclophosphamide, superiority was not demonstrated [30].
2.4 Cardiopulmonary manifestations

Pleuritis and pericarditis may respond to NSAIDs and steroids can be used in patients who do not respond to NSAIDs. Myocarditis usually requires high-dose prednisone (1 mg/kg/day).
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Intravenous immunoglobulin has been used successfully in life-threatening pericarditis [31]. Pulmonary hypertension is treated with vasodilatory agents and anticoagulants in addition to corticosteroids and cytotoxic agents to suppress inflammation. Traditionally, calcium channel blockers have been used for the management of pulmonary hypertension. Prostaglandin analogs used for management of pulmonary hypertension in SLE include intravenous epoprostenol (prostaglandin I2) and low-dose infusion or inhalation of iloprost (a prostaglandin I2 analog) [32-34]. Sildenafil, a phosphodiesterase inhibitor may be an effective treatment for lupus patients with pulmonary hypertension. Bosentan, an oral non-selective endothelin receptor antagonist, has recently become available for management of pulmonary hypertension [35,36]. Regular monitoring is required for possible abnormal liver function. The lack of selectivity of prostacyclins effects on pulmonary vasculature led to the development of inhaled therapy for pulmonary hypertension, which also has fewer systemic side effects. Repeated inhalation of iloprost has been shown to improve function and hemodynamics and to slow the rate of clinical decline [33,34].
2.5 Hematological

survival include the rapidity of the diagnosis of TTP, aggressive and early management with plasmapheresis in addition to active immunosuppression [42].
2.5.4

Antiphospholipid antibody syndrome

Patients with antiphospholipid antibody syndrome (APS) have a high risk of recurrent thromboses. Long-term anticoagulation is the best prophylactic treatment for recurrence of thromboses. Prophylactic treatment with aspirin during pregnancy reduced the risk of miscarriages significantly [43]. The results of the Aspirin for Primary Thrombosis Prevention in the Antiphospholipid Syndrome (APLASA) study indicate that asymptomatic antiphospholipid-antibody-positive individuals do not benefit from low-dose aspirin for primary thrombosis prophylaxis [44].
2.6 Neuropsychiatric lupus

Cytopenias including hemolytic anemia, thrombocytopenia and lymphopenia commonly occur in SLE and are immune mediated. When mild, they do not require any treatment, but when they become clinically significant, moderate- to high-dose steroids usually produce a response [37]. Anemia of chronic disease is present in up to 80% of SLE patients [38].
2.5.1

There are no controlled trials for the management of lupus psychosis. There have been several small studies, which have reported beneficial use of corticosteroids and different immunosuppressive therapies in patients with neuropsychiatric lupus. Neuropsychiatric symptoms like organic brain syndromes, psychosis, seizures, headaches, peripheral neuropathy and myelopathy require high-dose corticosteroids, such as intravenous pulse methyl prednisolone, 1 g daily for 3 days [15,45]. Pulse cyclophosphamide (1 g/m2) administered every 4 weeks may be effective in steroid-resistant cases [46]. Azathioprine can be used as a steroid sparing agent in CNS involvement in lupus [38].
3. Atherosclerosis prophylaxis

Hemolytic anemia, thrombocytopenia

Autoimmune hemolytic anemia is present in < 10% of patients [38]. The standard therapy is by using prednisone 1 2 mg/kg/day.; and intravenous methylprednisolone 1 g daily for 3 consecutive days when the hematologic abnormalities are life threatening. There have been several case series showing that MMF has been effective in the treatment of hemolytic anemia and thrombocytopenia [39]. There have been case reports proving the efficacy of rituximab in chronic idiopathic thrombocytopenic purpura and refractory thrombocytopenia [40,41]. Adjunctive measures in corticosteroid-resistant or -dependent patients with thrombocytopenia have included intravenous immunoglobulin and cyclosporine [37].
2.5.2

SLE patients are at high risk for atherosclerosis. Low-dose aspirin should be considered in patients with SLE receiving glucocorticoids, patients with positive antiphospholipid antibodies and in those with at least one traditional risk factor for atherosclerotic disease [47,48]. Lifestyle modifications including smoking cessation [49], weight control and exercise may be beneficial and should be encouraged.
4. Pregnancy

Leukopenia and lymphopenia

Leukopenia is seen in 50% of patients with SLE. Absolute lymphopenia is more common than neutropenia [38]. Lymphopenia could develop secondary to the disease activity or may occur as an adverse effect of treatment, such as steroids or immunosuppressants. The differentiation may be difficult when a patient on MMF develops a flare-up in the form of leucopenia.
2.5.3

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has been described in SLE. The most important factors that predict the
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Treatment of lupus in pregnancy is mainly with corticosteroids, since it is the least likely to cause adverse effects on the fetus. If lupus is active during the early part of the pregnancy, a poor outcome is highly likely. Therefore, patients should be counseled about using contraceptive measures and consider pregnancy only when the disease is in remission. Hydroxychloroquine, immunoadsorption and, on rare occasions, azathioprine has been used in pregnancy [50]. Cytotoxic agents like cyclophosphamide are known to be teratogenic and should be avoided during pregnancy. In women with APS and a history of previous fetal loss, anticoagulation in the form of heparin and aspirin should be given during pregnancy [48].

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5. New therapies in systemic lupus

5.3.1

B-cell depletion therapy

erythematosus

In SLE, autoreactive T cells stimulate proliferation of B cells and produce autoantibodies by the elevated levels of proinflammatory cytokines (TNF, IL-6 and IL-10) evident in patients with SLE [25]. IFN- is another cytokine that plays a crucial role in the pathogenesis of SLE. In the last decade there has been an improved understanding of the pathogenesis of SLE, and several newer agents have been developed for the management of SLE (Table 3).
5.1 Autologous hematopoeitic stem cell transplant

B cells have become a principal therapeutic target in SLE. Recent evidence indicates that B-cell-directed therapies are effective in lupus [56].
5.3.1.1 Anti-CD20 monoclonal antibody (rituximab)

The use of myeloablative cytotoxic therapy to fight the immunological insult followed by stem cell transplant has been performed effectively in aggressive forms of SLE [51]. The first hematopoeitic stem cell transplant for SLE was performed in 1997. ASCT demonstrated a high remission rate in a select group of patients with poor response. ASCT is not a cure for SLE but it may alter the severity of the disease to a more benign and more treatment-responsive state [52].
5.2 Hormonal therapies

SLE is a disease predominantly in women of child-bearing years. This information led to the investigation of hormonal mechanisms as potential targets for the treatment of SLE. The adrenal steroid hormone dehydroepiandrosterone (DHEA) has been studied in the treatment of SLE in multiple clinical trials and observational studies [53,54]. A large, placebocontrolled trial of DHEA was performed which showed that it enhanced the ability to taper prednisone when limited to patients with mild SLE [55]. Attempts have been made to downregulate prolactin using bromocriptine, a dopamine agonist, which selectively inhibits secretion of pituitary prolactin. Bromocriptine also suppressed early stage of T-cell activation and inhibited proliferation and immunoglobulin production in mitogen-stimulated human B cells. However, its use is limited to patients with hyperprolactinemia. The OC-SELENA trial showed that oral contraceptives were not associated with an increase in severe, mild to moderate or total flares over the course of 1 year compared with placebo. These data support the use of oral contraceptives containing estrogen as a birth control choice for patients with inactive or stable, moderate SLE who are at low risk for thrombosis.
5.3 Biological therapies

Rapid progress in the understanding of the pathogenesis of SLE has led to the development of new therapeutic agents that target each level of the chain of events leading to SLE. There have been therapies that target T cells, B cells, cytokines and complement. Three strategies have been investigated in humans which include B-cell targeting, cytokine blockade and costimulation blockade.

Rituximab is a chimeric monoclonal antibody (mAb) directed against CD20 antigen on B cells. Several studies have indicated that by selectively depleting B cells rituximab may be effective in reducing antibody production in SLE. CD20-targeted B-cell depletion in the treatment of SLE normalizes the disturbances in peripheral B-lymphocyte homeostasis which are characteristic of active disease [57,58]. There have been uncontrolled trials that showed that rituximab may be beneficial in patients resistant to standard immunosuppressive therapy and had a good safety profile [59]. There have been several case series that have reported successful treatment of resistant lupus manifestations with rituximab including CNS, renal vasculitic and hematological features. A Phase I/II dose escalation trial of rituximab showed that it is well tolerated in SLE and that B-cell depletion seems to be effective in reducing overall disease activity [60]. The majority of patients (11 of 17) had profound B-cell depletion, and clinical improvement lasted for 12 months despite the absence of a significant change in antidouble-stranded DNA antibody and complement levels [60]. In the same report, a single patient with class IV nephritis, proteinuria resolved completely in 1 year and a repeat renal biopsy showed complete resolution of previous proliferative pathology. There was another study consisting of 31 SLE patients with refractory lupus nephritis and autoimmune cytopenias where rituximab was added as a co-therapy and a complete B-cell depletion was achieved in all the patients. In the lupus nephritis patients complete or partial responses were achieved after 6 12 months. The responders were noted to have a shorter nephritis duration and detectable CD19 +ve B lymphocytes before therapy with rituximab. At present, multicenter, randomized Phase II/III clinical trials with rituximab in SLE are being conducted. In the EXPLORER trial, the clinical response to rituximab in combination with an immunosuppressive medication was compared with placebo in patients with moderate to severe disease as determined by BILAG. The EXPLORER trial enrolled moderately to severely active extrarenal SLE patients being evaluated for response to a new therapeutic agent. There were no statistically significant differences between rituximaband placebo-treated groups in the primary, secondary and exploratory end points in this population [50]. The LUNAR trial is an international study in patients with class III or IV lupus nephritis comparing rituximab with MMF and placebo.
5.3.1.2 Anti-CD20 monoclonal antibody (ocrelizumab)

Ocrelizumab is a new, humanized anti-CD20 antibody, which has demonstrated enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared with rituximab [61,62]. Ocrelizumab binds to a different, but overlapping, epitope of the extracellular
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Table 3. New therapies in systemic lupus erythematosus (sle).

Targets T-cell targets Mechanism of action CD4 CD40 ligand CTLA4Ig CD20 CD22 BlyS TACI Ig B-cell tolerogen DNA binding peptide Interferon- Interleukin-10 Interleukin-6 Interleukin-1 C5 C3 Inhibits mTOR Stimulates de novo biosynthesis Block T-cell hyperactivity Therapy Anti-CD4 Anti-CD40 ligand Abatacept Anti-CD20 (rituximab, ocrelizumab) Anti-CD22 (epratuzumab) Anti-BlyS (belimumab) TACI Ig fusion protein (atacicept) LJP 394 (abetimus sodium) Anti-IFN- (MEDI-545) Anti-IL-10 (B-N10) Anti-IL-6 (tocilizumab) Anti-IL-1 Anti-C5b mAb C3 complement inhibitor Rapamycin N-acetyl cysteine Edratide Ref.
[39] [68] [39] [59,62] [63] [39] [110] [66,68] [56,77] [56,88,89] [56] [90,91] [93] [94] [75] [103] [72]

B-cell targets

Cytokine targets

Complement targets mTOR GSH depletion T-cell tolerogen

domain of CD20. Phase III clinical trials are ongoing to evaluate the efficacy and safety of ocrelizumab added to SOC (corticosteroid plus one of two immunosuppressant regimens) compared with placebo added to SOC in patients with WHO or ISN class III or IV lupus nephritis [62].
5.3.2

Anti-CD22 monoclonal antibody (epratuzumab)

An open-label study was conducted in 14 SLE patients with BILAG scores ranging from 6 to 12, and they were given four doses of epratuzumab at 360 mg/m2 at 2-week intervals. The BILAG scores improved in all patients, with 77% achieving 50% improvement from the baseline scores at 6-week follow-up. The infusions were well tolerated after premedication with acetaminophen [63]. This was a short-term study in a small group of patients, and a new multicenter international Phase III study was commenced in 2007 to study this mode of therapy further. Epratuzumab preferentially modulates the exaggerated activation and proliferation of B cells from patients with lupus in contrast to normal subjects. A pronounced reduction of CD27-B cells and CD22 surface expression on CD27-B cells was observed, suggesting that these cells, which mainly comprise naive and transitional B cells, are preferentially targeted by epratuzumab in vivo [64].
5.3.3

was no significant benefit in preventing renal flare [66-68], but treatment with abetimus sodium was associated with a reduction in antidsDNA levels and a 50% reduction in 24-h protein levels after 1 year of treatment. Treatment with abetimus sodium also resulted in 21% lower incidence of major SLE flares and improved SLEDAI scores over time compared with placebo. Twenty-five per cent fewer renal flares occurred in the abetimus group compared with the placebo group throughout the trial [69]. Since March 2006, there has been an ongoing randomized, double-blind, placebo-controlled, multicenter trial recruiting patients with active lupus nephritis to determine whether LJP 394 (300 mg and 900 mg i.v. infusions weekly over 52 weeks) is more effective than placebo in delaying the time to renal flare. This Phase IIIb clinical trial using LJP-394 was discontinued owing to lack of efficacy revealed during interim analysis.
5.3.4

Anti-B lymphocyte stimulator

Anti-B lymphocyte stimulator (BlyS) is a member of the TNF cytokine family present on B cells.
5.3.4.1 Animal studies

Lymphostat-B (belimumab), a fully human mAb directed against BlyS, was studied in murine lupus models and resulted in increased survival.
5.3.4.2 Human studies

B cell tolerogen Abetimus sodium (Riquent/LJP 394)

Abetimus sodium is a complex molecule consisting of four 20 mer dsDNA epitopes linked to an inert triethylene glycol platform. It was hypothesized that abetimus sodium might block production of antidsDNA antibodies. This was tested in a large, double-blind, placebo-controlled trial of patients with lupus nephritis [65]. LJP 394 has been evaluated for treatment and prevention of nephritic flares in SLE. There
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A Phase I, single- and double-dose escalation trial in 57 patients who had stable SLE showed a significant reduction in B cells but no change in SLE activity [39]. Preliminary results from a Phase II clinical trial enrolling 449 SLE patients with moderate disease activity show improvements in disease-activity and quality-oflife scores [70]. A Phase III anti-BlyS study is now ongoing.

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5.3.5

Atacicept

Atacicept is a TACI Ig fusion protein that inhibits B-cell stimulation by binding to B-lymphocyte stimulator and a proliferation inducing ligand. Atacicept administered subcutaneously was well tolerated and demonstrated biological activity in this preliminary study, and will be evaluated further in a Phase II/II trial [71].
5.3.6

Edratide

Edratide (TV-4710) is a T-cell tolerogen synthetic peptide derived from the Vh region of human immunoglobulin specific for dsDNA. Edratide, which was thought to block T-cell hyperactivity, did not meet its primary end point in the PRELUDE trial. Edratide, administered as a subcutaneous weekly injection, was shown to be safe and well tolerated. PRELUDE, a randomized, double-blind, placebo-controlled, parallel assignment Phase II study was designed to assess the efficacy and safety of edratide, with the primary end point being the reduction of lupus disease activity over a 26-week treatment period, as measured by the SLEDAI score [72]. Edratide did not meet the efficacy end points in clinical trials.
5.3.7

with infliximab developed an increase in autoantibodies to nuclear antigens and phospholipids. These increases were transient and were not associated with disease activity [76,77]. In an open safety study, six patients with SLE (4 with nephritis) were treated with infliximab (a chimeric mAb to TNF-) in addition to other immunosuppressives and steroids [78]. There was a significant and sustained reduction in proteinuria with stable creatinine levels at 6 months. The improvement in articular manifestations was more transient with relapses after discontinuation of treatment [79]. A Phase II study is now ongoing to evaluate the efficacy of TNF blockers in SLE. There have been several reports of lupus that developed in patients treated with TNF inhibitors. These patients developed autoantibodies, rash, general symptoms like fatigue, oral ulcers, serositis, nephropathy, CNS involvement and arthritis [80]. Some patients developed a clinical presentation indistinguishable from spontaneous SLE. In these patients, it is possible that biologic agents may act as a triggering factor of a possible underlying or subclinical SLE, resembling the lupus flares triggered by exposure to sunlight, exercise or pregnancy [80].
5.3.9

Anticytokine therapies

Agents that target costimulatory pathways

5.3.9.1 Anti-IFN- monoclonal antibodies

Agents that have been tested in clinical trials in human lupus include anti-CD40 ligand and cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) [39].
5.3.7.1 Cytotoxic T-lymphocyte-associated antigen

4-immunoglobulin (CTLA4Ig or abatacept)

CTLA4Ig is a fusion protein of the extra cellular domain of the T lymphocyte antigen 4 and the Fc portion of IgG1 which inhibits T-cell activation [39]. An international, multicenter, randomized, double-blind, placebo-controlled Phase II clinical trial in SLE to evaluate the safety and efficacy of abatacept in treatment of mild to moderate SLE, cutaneous lupus flares, lupus arthritis and/or serositis is underway [56]. In a Phase II study using abatacept in patients with moderate to severe SLE, the adjudicated BILAG-based primary and secondary end points were not met [73].
5.3.7.2 Anti-CD40 ligand

Elevated serum levels of IFN- are found in patients with SLE, where they correlate with both disease activity and severity [81]. Animal studies in IFN-/ receptor-depleted mice revealed a significant reduction in the production of anti-DNA antibodies, with a reduced prevalence of hemolytic anemia, kidney involvement and mortality [82]. Anti-IFN- agent MEDI-545, a fully human mAb directed against IFN- has been evaluated by a Phase I, randomized, double-blind, dose-escalation study in patients with SLE. The results have not yet been published [83]. The results of a dose-finding study of MEDI-545 were presented at ACR 2007 and showed that MEDI-545 inhibited the interferon signature and showed clinical efficacy in disease activity, flares and steroid sparing [113]. MEDI-545 showed proof of concept that it inhibited the interferon signature in a dose-finding study. Fifty per cent of SLE patients have the interferon signature. It showed clinical efficacy in disease activity, flares and steroid sparing [84].
5.3.9.2 Anti-IL-6 monoclonal antibodies

Murine experiments have demonstrated over expression of CD-40 ligand (CD40L) on T cells of SLE mice and showed that early anti-CD40L therapy delayed disease onset by reducing B-cell activation markers, autoantibody production and renal immune complex deposition [74,75]. However, expression of CD40L is not confined to T cells. Owing to its expression on platelets [68], there was an increased incidence of thromboembolic complications with anti-CD40L treatment, and a trial in patients with proliferative lupus nephritis had to be terminated early [68].
5.3.8

Anti-TNF- therapies

TNF blockers seemed to be clinically effective in small, open-label studies. The majority of SLE patients treated

IL-6 is secreted predominantly by macrophages and T cells. IL-6 induces B-cell differentiation to plasma cells, T-cell proliferation and cytotoxic T-cell differentiation and local inflammation. The serum concentrations of IL-6 are increased in SLE. Tocilizumab, a humanized mAb directed against IL-6 receptor was studied in an open-label, dose-escalating, Phase I study in SLE patients. Sixteen SLE patients with mild to moderate disease activity (SLEDAI scores 4 15) were given three doses of i.v. tocilizumab (2, 4 and 8 mg/kg) biweekly for 12 weeks. At 14 weeks, SLEDAI and SLAM scores improved but three patients required increases in prednisone dosage for minor flares [56,85,86].
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5.3.9.3 Anti-IL-10 monoclonal antibodies

IL-10 has been implicated in B-cell hyperactivity and autoantibody secretion in patients with SLE. B-N10, a murine antiIL-10 mAb that neutralizes human IL-10 has been developed. In a small study, six steroid-dependent SLE patients received intravenous doses of 20 mg of B-N10 daily during a 3-week period. All subjects developed antibodies against B-N10. At 6 months, significant improvement in SLEDAI was demonstrated and disease was clinically inactive in five patients despite the large reductions in corticosteroid treatment [56,87-89].
5.3.9.4 Anti-IL-1 monoclonal antibodies

inhibition may provide a new therapeutic option in lupus cerebritis [95].

5.5 Mitochondrial dysfunction in lupus T cells

Recombinant IL-1 administered in mice models increased nephritis and when the mice were given a recombinant receptor type 1 there was a decrease in the production of autoantibody and delayed onset of nephritis [90,91]. Open-label trials with anakinra have shown that it might be a therapeutic alternative for individual patients with SLE and active joint involvement or Jaccouds arthropathy not responding to treatment [112]. Further controlled trials are needed to study the long-term effects of IL-1 blockade [92].
5.4 Blocking of complement activation

Complement plays an important role in the immune-complexbased inflammatory reaction that damages the kidney in lupus nephritis.
5.4.1

SLE is characterized by abnormal T-cell activation and death, processes that are crucially dependent on the controlled production of reactive oxygen intermediates (ROI) and of ATP in mitochondria [96]. The mitochondrial transmembrane potential (m) has conclusively emerged as a critical checkpoint of ATP synthesis and cell death. Lupus T cells exhibit persistent elevation of m or mitochondrial hyperpolarization (MHP) as well as depletion of ATP and glutathione, which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE [75,97]. Persistent MHP is associated with increased mitochondrial mass and increased mitochondrial and cytoplasmic Ca2+ content in T lymphocytes and also with enhanced nitric oxide (NO) production in monocytes. NO-induced mitochondrial biogenesis in normal T cells accelerates the rapid phase and reduces the plateau of Ca2+ influx upon CD3/CD28 costimulation, thus mimicking the Ca2+ signaling profile of lupus T cells [98]. Understanding the molecular basis and consequences of MHP is essential for controlling abnormal T-cell activation and death signaling in SLE.
5.5.1

Blocking of mTOR activation with rapamycin

Anti-C5b monoclonal antibody

The mAb to C5 blocks the late membrane attack complex of complement (C5b-9), delays the onset of proteinuria, improves renal histology and prolongs survival, when administered to NZB/W mice [93].
5.4.2

C3 complement inhibitor

The targeted murine C3 complement inhibitor, CR2-Crry, when administered to mice from 16 24 weeks of age after the development of proteinuria causes complement inhibition locally without causing systemic inhibition. Administration of CR2-Crry intravenously at a dose of 0.25 mg once a week was associated with a significant survival benefit, improved kidney function and a significant reduction in glomerulonephritis and renal vasculitis. CR2-Crry treatment also reduced skin lesions, lung bronchiolar and vascular inflammation and a significant reduction in autoantibody production as measured by antidsDNA levels [94]. Cerebral water content is regulated by aquaporin 4 present in astrocytic feet around blood vessels. Increased aquaporin 4 expression results in cerebral edema. Activation of complement may play a significant role in the pathogenesis of lupus cerebritis by causing inflammation that can lead to edema. In the lupus mouse model, IgG and C1q colocalized in perivascular deposits, indicating that the bloodbrain barrier was compromised. Chronic administration of the soluble complement inhibitor, Crry-Ig, reduced inflammation as measured by decreased accumulation of IgG. Hence complement
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The mammalian target of rapamycin (mTOR) is located in the outer mitochondrial membrane and serves as a sensor of the m in T cells. Focused on targeting MHP in lupus patients resistant or intolerant to conventional immunosuppressants, rapamycin improved disease activity and normalized baseline and T-cell activation-induced Ca2+ fluxing without affecting MHP in patients with SLE. Indeed, mTOR activity is increased in lupus T cells. These findings indicated that mTOR may represent a gate keeper between MHP and altered Ca2+ signaling in SLE [99,100].
5.5.1.1 Animal studies

Rapamycin has been shown to normalize T-cell mitogenstimulated splenocyte proliferation and IL-2 production, prevent the rise of antidouble-stranded DNA antibody, urinary albumin levels and glomerulonephritis and prolong survival in lupus-prone mice [96,101].
5.5.1.2 Human studies

In a study conducted at our institution, nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive agents were treated with rapamycin, 2 mg daily oral dose. Rapamycin was well tolerated and proved effective in controlling the disease activity in all nine patients. Arthritis improved in all nine patients, and nephritis in three patients remained in remission during rapamycin treatment [102]. Rapamycin, also called sirolimus (rapamune), has been approved by the FDA to prevent rejection of organ transplants

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at daily doses of 2 8 mg. Patients that were resistant or intolerant to conventional medication have been effectively treated with Rapamycin and were able to decrease the amount of prednisone used. A Phase II clinical trial is underway at our institution to assess the efficacy of rapamycin for the treatment of SLE.
Normalizing glutathione depletion with oral N-acetyl cysteine (NAC)
5.5.2

6. Monitoring of drug safety and side effects

in patients with sle

Current evidence indicates that a natural antioxidant, glutathione (GSH) is depleted in T cells of patients with SLE. Depletion of GSH predisposes to MHP and ATP depletion that promote proinflammatory T-cell death by necrosis [75].
5.5.2.1 Animal studies

Administration of N-acetyl cysteine (NAC) that serves as a precursor of glutathione and stimulator of its de novo biosynthesis improves the clinical outcome of murine lupus and limits the toxicity of immunosuppressant medications commonly used in patients with SLE. Recent studies showed that treatment with NAC prevented the decline of GSH, reduced autoantibody production and development of glomerulonephritis and prolonged the survival of (NZBxNZW) F1 mice [103].
5.5.2.2 Human studies

Patients with SLE need close monitoring and follow-up. The frequency of the follow-up visits should be determined by the severity of the disease. Patients should be evaluated for clinical disease activity and complications from treatment at each visit. Patients on hydroxychloroquine should get regular ophthalmologic assessments (every 6 12 months) to detect retinal toxicity from the drug. Patients on long-term steroids should undergo evaluation for osteoporosis with a bone densitometry. They should be started on an osteoporosis prevention program with calcium and vitamin D supplements and bisphosphonates. Patients receiving immunosuppressive or cytotoxic medications (methotrexate, azathioprine, cyclophosphamide) should be monitored carefully for evidence of hematologic and liver toxicity.
7. Conclusions

In a 1-year study of patients with inflammatory lung disease treated with prednisone and azathioprine, addition of NAC (1.8 g/day) diminished disease severity and reduced drug toxicity compared with placebo [104]. A Phase I/II trial is underway to assess the safety and efficacy of NAC treatment in SLE [105,106].
5.6 Dezoxyribonuclase (DNAse)

Current management of SLE involves the use of immunosuppressive medications, some of which have not been tested in randomized, controlled trials. These medications have serious adverse effects including predisposition to infections, malignancies and anemia. With the advent of biologicals, the side effects may be related to the mechanism of intervention; for example, B-cell depletion inhibits the maturation of B cells to autoantibody-producing plasma cells but also predisposes to infections normally eliminated through humoral immunity. A more profound understanding of disease pathogenesis and the mechanism of action of the employed medications and careful monitoring of clinical activity and drug side effects are required for the effective management of patients with SLE.
8. expert opinion

DNAse is an enzyme produced by the pancreas and salivary glands that catalyses the hydrolysis of excessive extracellular DNA. It was hypothesized that DNAse prevents deposition of immune complexes containing DNA and promote their clearance from affected tissues. In mouse models, a murine DNAse showed a reduction in proteinuria and serum creatinine with an improvement in renal histology. In a randomized, doubleblind, placebo-controlled trial, 16 patients with lupus nephritis (class III, IV and V) were given treatment with a recombinant human DNAse (rhDNAse) for 40 days. No clinical efficacy was demonstrated but it was well tolerated and there was no production of antibodies to rhDNAse [107]. Further trials are warranted to test its efficacy and safety.
5.7 Gene therapy

Gene therapy for SLE is in very early stages of development. It has been possible to alter the disease course in murine SLE by intramuscular injection of naked DNA encoding cytokines. As an example, gene transfer of CTLA4-Ig to NZB/W F1 mice delayed autoantibody formation and proteinuria [90,108].

The 5-year survival rate has dramatically increased over the last several decades from approximately 40% in the 1950s to more than 90% in studies starting after 1980 [109]. The improvement in patient survival is multifactorial: earlier diagnosis with more sensitive diagnostic tests, early and more decisive immunosuppression and close monitoring and prompt treatment of complications. The introduction of pulse cyclophosphamide treatment for lupus nephritis and advances of hemodialysis techniques have played a pivotal role in improving the survival of patients with SLE [51]. In spite of these improvements, 10% of SLE patients still die within the first 5 years of diagnosis and their mean life expectancy is still shorter than the general population, which may be due to relentlessly progressive disease in some patients, despite all available treatments, and also to sequelae of treatment, especially immunosuppressive therapy [51]. Almost 40 years have gone past since the last drug was approved by the FDA specifically for the treatment of lupus
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Anti-IFN Anti-IL-6 IFN Anti-IL-10 Anti-Blys CTLA4Ig Blys CD28 T Necrotic debris/HMGB1 CD40L Treg Rapamycin Anti-CD40 ligand NAC CD22 TACI-Ig CD80/86 B CD20 LJP 394 (DNA mimic) Anti-CD20 IL-10

IL-6 APC/DC macrophages

Anti-DNA antibody

Anti-CD22

Figure 1. Biomarker-driven therapeutic targets in systemic lupus erythematosus (sle). A schematic diagram of abnormal immune responses and biomarkers targeted for treatment in SLE. Necrotic materials, such as HMGB1, are released from T cells, which in turn activate DC. DCs produce IFN-. Macrophages, DCs and B cells show elevated expression of costimulatory molecules CD80/CD86 and thus contribute to T-cell activation [83]. Monoclonal antibodies against CD20 (rituximab) cause death of B cells. Antibody to CD22 (e.g., epratuzumab) also causes B-cell death. B-cell tolerogens such as LJP 394 crosslink B-cell receptors and cause B-cell anergy or deletion [98]. Monoclonal antibodies against the cytokine BlyS cause inhibit B-cell survival. Monoclonal antibodies against CD40L blocks costimulatory interaction between T and B cells. CTLA4Ig inhibits the CD28-CD80/CD86 costimulatory pathway.
APC: antigen presenting cells; BlyS: B lymphocyte stimulator; DC: dentritic cells; HMGB1: high mobility group protein B1; IFN-, interferon-; IL-6: interleukin-6; IL-10: interleukin-10; T reg: regulatory T cells.

(hydroxychloroquine in 1969). Often, therapies that have been inadequately studied are used off label for the management of SLE. In the past decade, there has been an improved understanding of the molecular pathogenesis of SLE and there have been several developments capitalizing on this knowledge. This has resulted in a new generation of potential SLE treatments with more specific targeting of the immune system [110]. The traditional treatment of SLE was based on global immunosuppression, but the novel therapies being developed at present target specific steps in the pathogenesis of SLE. Figure 1 depicts the specific targets that are now under investigation [99]. IFN- levels are known to be elevated in SLE. Studies in animal models have shown that when IFN- was depleted there was decreased production of autoantibodies with reduced renal involvement and mortality [81,82]. Evidence for a beneficial role by TNF blockers in SLE patients is still limited. A small, open-label study of infliximab (TNF blocker) in SLE showed significant improvement in patients with refractory lupus nephritis, but this was associated with elevation of antidsDNA antibodies. It may be used for short-term induction, but controlled trials are needed to evaluate its efficacy and safety of long-term TNF blockade [77,79]. Rapamycin was well tolerated and was effective in controlling disease activity in a small group of lupus patients [96,101,102]. Phase II clinical trials are now ongoing
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for the evaluation of rapamycin in the management of SLE [105]. Administration of N-acetyl cysteine (NAC), which serves as a precursor of glutathione and stimulator of its de novo biosynthesis, improves the clinical outcome of murine lupus and limits the toxicity of immunosuppressant medications commonly used in SLE patients [75]. A Phase I/II trial is underway to assess the safety and efficacy of NAC treatment in SLE [105,106]. IL-6 levels are elevated in SLE. Administration of IL-6 mAb reduced proteinuria and prolonged survival in mice [109]. CTLA4-Ig is a fusion protein of the extracellular domain of the T-lymphocyte antigen 4 and the Fc portion of IgG1, which causes T-cell activation. Studies in murine lupus showed decreased proteinuria and prolonged survival [39,56]. A Phase II clinical trial on SLE to evaluate the safety and efficacy of abatacept in the treatment of mild to moderate SLE cutaneous lupus flares, lupus arthritis and/or serositis is underway [56]. New approaches that target B cells also show great promise in the management of SLE. Rituximab is an anti-CD20 mAb that has been proven to be effective in small studies [57,59]. Phase III trials are now being conducted to evaluate the efficacy in moderate to severe lupus flares and in lupus nephritis. Belimumab is a human mAb that recognizes BlyS and reduces B-cell proliferation and differentiation in animal models. In a Phase I study, one or two doses of belimumab produced a significant reduction in the percentage of CD20

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B cells, but there was no significant decrease in SLE disease activity [39].The anti-CD22 mAb epratuzumab produced only a modest fall in circulating B cells and the serological changes in biological markers was not remarkable [91]. According to the most recently published data from ACR 2008, neither rituximab nor abatacept showed efficacy in the randomized clinical trials [73,86]. It has to be admitted that we have experienced several setbacks in the search for optimum therapy for lupus. The therapeutic blockade of anti-CD40 ligand showed promise in animal studies but clinical trials showed disappointing results with high incidence of thromboembolic events [68]. A trial of edratide, a new tolerogenic peptide thought to alter T-cell function, did not meet the primary end point based on the SLEDAI

scoring system) [72]. The recent EXPLORER trial comparing the use of intravenous rituximab with placebo infusion failed to show any benefit using the BILAG or SLEDAI disease activity indexes in SLE patients without renal disease [58]. In summary, although we have come a long way in improving disease outcomes in patients with SLE, a tremendous amount of work remains to be done towards a better understanding of disease pathogenesis to identify and test better treatment targets with the ultimate goal to cure lupus.

Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Affiliation
Lisa Francis & Andras Perl Author for correspondence Division of Rheumatology, Department of Medicine, SUNY, 750 East Adams Street, Syracuse, NY 13210, USA Tel: +1 315 464 4194; Fax: +1 315 464 4176; E-mail: perla@upstate.edu

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