Back to Journals » ImmunoTargets and Therapy » Volume 5

Current and emerging treatment options in the management of lupus

Authors Jordan N, D'Cruz D 

Received 20 August 2015

Accepted for publication 24 November 2015

Published 2 March 2016 Volume 2016:5 Pages 9—20

DOI https://doi.org/10.2147/ITT.S40675

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Michael Shurin



Natasha Jordan,1 David D’Cruz2

1Department of Rheumatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, 2Louise Coote Lupus Unit, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with variable clinical manifestations. While the clearest guidelines for the treatment of SLE exist in the context of lupus nephritis, patients with other lupus manifestations such as neuropsychiatric, hematologic, musculoskeletal, and severe cutaneous lupus frequently require immunosuppression and/or biologic therapy. Conventional immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are widely used in the management of SLE with current more rationalized treatment regimens optimizing the use of these agents while minimizing potential toxicity. The advent of biologic therapies has advanced the treatment of SLE particularly in patients with refractory disease. The CD20 monoclonal antibody rituximab and the anti-BLyS agent belimumab are now widely in use in clinical practice. Several other biologic agents are in ongoing clinical trials. While immunosuppressive and biologic agents are the foundation of inflammatory disease control in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected.

Keywords: hydroxychloroquine, mycophenolate mofetil, azathioprine, cyclophosphamide, rituximab, belimumab

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, with variable clinical manifestations, that follows an unpredictable relapsing remitting course. In the past, the main causes of death in SLE patients were uncontrolled inflammatory disease activity and infection due to immunosuppression.1 While patients may still succumb to these complications, early atherosclerotic disease has become a major cause of morbidity and mortality in patients with SLE.2

It is now well recognized that cumulative organ damage, in particular renal damage, is an important predictor of mortality in SLE.3 Recurrent flares of disease activity such as lupus nephritis are associated with poor long-term outcomes.4,5 There remains an unmet clinical need in SLE, particularly in patients with disease refractory to conventional immunosuppressive therapies. Another key issue in the therapeutic management of SLE is the longstanding overreliance on corticosteroid therapy which contributes substantially to damage accrual and patient mortality. In this review, we focus on therapeutic advances in the management of SLE with a discussion of recent optimizations in the use of established immunosuppressive therapies and an overview of new biologic agents.

Conventional immunosuppressive agents in the management of SLE

Induction and maintenance therapies in lupus nephritis

Immunosuppressive treatment of lupus nephritis is divided into induction and maintenance phases. There are a number of existing guidelines for the treatment of lupus nephritis including the American College of Rheumatology and European League Against Rheumatism guidelines, which are in agreement on some areas of lupus nephritis management, but differ in others.6,7

The aims of induction therapy in lupus nephritis are to initiate immunosuppressive therapy without delay and achieve remission of renal disease in terms of proteinuria and renal function as promptly as possible. Definitions of partial and complete renal response vary somewhat in different treatment guidelines and as endpoints in clinical trials.

The aims of maintenance therapy in lupus nephritis are consolidation of renal response achieved during induction therapy, prevention of disease flares, and prompt identification of disease relapse, ultimately leading to long-term preservation of renal function. There are no data to guide the appropriate duration of maintenance therapy beyond 3 years and hence treatment should be tailored to the individual patient. Ideally, corticosteroid should be tapered and when possible withdrawn before immunosuppression is tapered. In both the induction and maintenance phases of lupus nephritis management, avoidance of treatment-related toxicity is essential for improved quality of life and patient survival.

The main therapeutic options for induction therapy of lupus nephritis are mycophenolate mofetil (MMF) and cyclophosphamide (CYC), which are generally given with concurrent corticosteroid therapy. MMF and CYC are considered equivalent in terms of efficacy and frequency of adverse events based on clinical trials.810 Unlike CYC, MMF does not adversely affect fertility, although both agents are absolutely contraindicated in pregnancy due to teratogenicity. Patients of different ancestral backgrounds may respond differently to therapy with evidence that African and Hispanic lupus nephritis patients respond less well to intravenous CYC than Caucasian or Asian patients, thus MMF may be a more preferable choice for induction therapy in these groups.8,11,12

It should be noted that the response to treatment with MMF versus CYC seems to be very dependent upon the treatment center. Some centers have consistently good results with MMF but poor results with CYC, while the opposite holds true in other centers. Some physicians adjust the CYC dose according to the trough white cell count 10–14 days after the infusion to ensure that the therapeutic benefit of the drug is achieved.

There are two widely used regimens of intravenous CYC as induction therapy for lupus nephritis; the low-dose Eurolupus regimen (500 mg once fortnightly for 3 months), and the high-dose NIH regimen (500–1,000 mg/m2 intravenously monthly for 6 months).1315 The long-term results of these CYC regimens are comparable in terms of safety and efficacy.1618 The Eurolupus regimen may be preferable in patients of European ancestry.

The main choices for maintenance therapy in lupus nephritis are azathioprine (AZA) or MMF, which have been shown to have similar efficacy and frequency of adverse events in clinical trials, although one large study showed superiority of MMF over AZA.13,16,19 As part of the decision-making process as to which maintenance therapy to use, the patients’ future desire to become pregnant must be considered as MMF is known to be teratogenic whereas AZA is widely used in pregnancy.20 The optimal duration of maintenance therapy in lupus nephritis before tapering or withdrawal is as yet unknown and is currently at the treating physician’s discretion.

Calcineurin inhibitors may provide a useful adjunctive therapy in lupus nephritis. A recent Chinese study comparing MMF in combination with tacrolimus was proven to be superior to intravenous CYC in terms of achieving complete renal remission.21 In a previous study, tacrolimus was found to be noninferior to MMF when combined with prednisolone for induction therapy of active lupus nephritis.22 When followed by AZA maintenance for 5 years, a trend toward higher incidence of renal flares and decline in renal function was observed in those who received tacrolimus induction therapy.23 Tacrolimus may be particularly useful as adjunctive therapy in patients with persistent proteinuria despite other therapies, and in the management of lupus nephritis in pregnancy.24

Immunosuppression in nonrenal lupus

Neuropsychiatric lupus

The approach to the management of neuropsychiatric lupus depends on the underlying etiology which may be inflammatory, thromboembolic, or neurotoxic in origin. Clinical manifestations such as cerebral vasculitis, aseptic meningitis, optic neuritis, transverse myelitis, refractory seizures, acute confusional state, and psychosis are frequently driven by inflammation and may be managed with immunosuppression. Unlike lupus nephritis, there is a paucity of randomized controlled trials in neuropsychiatric lupus given the heterogeneity of clinical manifestations and lack of standardization of outcome measures. In 2010, the European League Against Rheumatism published recommendations for the management of neuropsychiatric manifestations in SLE.25 On the basis of published case series, one nonrandomized clinical trial, and numerous case reports, intravenous CYC is the treatment of choice for severe neuropsychiatric lupus manifestations.2633 Similar to lupus nephritis, AZA and MMF are frequently used as maintenance therapies for neuropsychiatric lupus.34,35

Inflammatory arthritis and myositis related to lupus

Hydroxychloroquine and corticosteroids remain first-line therapies for musculoskeletal manifestations of SLE; however, patients with severe inflammatory arthritis and myositis may require further management with immunosuppressive or biologic agents for inflammatory disease control.

Methotrexate (MTX), which is the disease-modifying therapy of choice in rheumatoid arthritis, has been shown to be effective in controlling inflammatory arthritis related to lupus in clinical trials, case series, and several case reports.3639 In patients unable to tolerate MTX, leflunomide may be considered for treatment of inflammatory arthritis related to lupus.40,41 MMF and to a lesser degree AZA have shown efficacy in the treatment of inflammatory myositis in SLE patients and have demonstrated a steroid sparing effect.4244 In severe lupus-related inflammatory myositis refractory to corticosteroids and other immunosuppression, intravenous CYC has been used with some success.42,45

Severe cutaneous lupus

Severe cutaneous lupus may present as acute, subacute lupus erythematosus, discoid lupus erythematosus, lupus panniculitis, and lupus cutaneous vasculitis. Topical corticosteroids and immunomodulators such as topical tacrolimus and pimecrolimus, antimalarials such as hydroxychloroquine or mepacrine, and corticosteroids remain first-line therapies.

A number of randomized controlled trials and case series have shown the effectiveness of MTX in managing severe cutaneous lupus at doses ranging from MTX 10 to 25 mg per week.4649 Both AZA and MMF have been used to good effect in cases of recalcitrant cutaneous lupus.5054

Dapsone, an immunomodulatory agent, has been shown to be effective in a number of cutaneous lupus forms including bullous lupus erythematosus, lupus panniculitis, subacute lupus erythematosus, and discoid lupus erythematosus.55 Dapsone can cause dose-related hemolysis and patients should be screened for glucose-6-phosphate dehydrogenase deficiency prior to commencing this medication.

Thalidomide has also been used with some success in the treatment of cutaneous lupus.56 Thalidomide is known to be teratogenic and hence female patients of childbearing age need to be taking an effective form of contraception while on this medication.

Biologic therapies, particularly rituximab and belimumab, have shown good promise in treating cutaneous lupus unresponsive to conventional immunosuppression and will be discussed in detail further on in this review.

Severe hematologic manifestations of SLE

Immune-mediated cytopenias such as thrombocytopenia, leucopenia, and hemolytic anemia frequently occur in lupus patients. Corticosteroids and immunosuppressive agents may be prescribed to manage these hematological manifestations of SLE. AZA and MMF have both been used to good effect in severe refractory lupus-related thrombocytopenia, leucopenia, and hemolytic anemia, with a steroid-sparing effect.57,58 Intravenous CYC has been used with success in the treatment of autoimmune thrombocytopenia unresponsive to standard treatment.59,60 Intravenous immunoglobulin has been shown to have a good therapeutic response in SLE patients with hematologic manifestations such as autoimmune thrombocytopenia and hemolytic anemia.61,62 Biologic agents particularly rituximab have been used in refractory cases of hematologic lupus. The BLISS-52 and BLISS-76 Phase III trials of belimumab in SLE have shown efficacy in treating hematologic manifestations of SLE and will be discussed in detail later in this review.

The advent of biologic therapies in the management of SLE

In recent years, an increased understanding of the etiopathogenesis of SLE has led to the introduction of a number of biologic agents that specifically target disease pathways underlying the development and progression of lupus. These biologic agents can be broadly categorized into those directed at B-cells and non-B-cell targets. Some of these therapies such as rituximab and belimumab have entered the realm of clinical practice while others are in ongoing clinical trials.

B-cell depletion with rituximab

Rituximab is a chimeric monoclonal antibody which selectively targets B-cells with the surface marker CD20. Rituximab is widely used for the treatment of SLE in clinical practice but remains unlicensed. It has been found to be particularly useful in SLE patients with recalcitrant disease including renal, hematologic, and cutaneous manifestations. A number of published case series and open label trials of rituximab in SLE patients have demonstrated beneficial results in these areas.6367 However, it is unclear whether rituximab is exclusively working via B-cell depletion, as it may have additional effects via binding of Fc gamma receptor IIB on B-cells and macrophages, thus inhibiting their activation.

A significant setback to the more widespread acceptance of rituximab in the treatment of SLE was the failure of two pivotal randomized controlled trials. Both the EXPLORER study of rituximab in nonrenal SLE and the LUNAR study in lupus nephritis failed to achieve their primary endpoints.68,69 On a more positive note, a recent prospective observational study of rituximab as part of a corticosteroid sparing regimen in lupus nephritis has shown encouraging results.70

Clinical experience to date has found rituximab to be generally safe and well tolerated. However, infusion reactions, allergic or anaphylactic reactions, severe or recurrent infections, and progressive multifocal leuco-encephalopathy have been reported in rituximab-treated SLE patients (Table 1).71,72

Table 1 B-cell targeted biologic therapies in SLE
Note: #Information regarding ongoing clinical trials in SLE obtained from ClinicalTrials.gov.
Abbreviations: BEL, belimumab; CYC, cyclophosphamide; Ig, immunoglobulin; MMF, mycophenolate mofetil; RITUX, rituximab; SLE, systemic lupus erythematosus; APRIL, a proliferation-inducing ligand; BLyS, B lymphocyte stimulator; TACI, TNF transmembrane activator and calcium modulator and cyclophilin ligand interactor; TNF, tumor necrosis factor; BAFF, B-cell activating factor.

Targeting B-cell survival with belimumab

B lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor (TNF) ligand superfamily and play key roles in the regulation of B-cell proliferation, differentiation, and immunoglobulin secretion.77,78 BLyS exists in both membrane bound and soluble forms and is expressed by cells of the innate immune system such as monocytes, macrophages, and dendritic cells. BLyS can bind to three receptors, all of which are expressed by B-cells, including TNF transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B lymphocyte maturation antigen (BCMA), and BAFF/BLyS receptor 3 (BR3).79,80 Plasma and peripheral blood leukocyte mRNA BLyS levels have been shown to correlate with disease activity and autoantibody levels in SLE patients.81,83

Belimumab is a monoclonal antibody targeting BLyS that has been shown to be safe and efficacious in two large randomized controlled trials in SLE, the Belimumab International SLE Studies, BLISS-52, and BLISS-76.84,85 Both of these studies excluded SLE patients with active lupus nephritis or neuropsychiatric disease.

A post hoc analysis of the organ domain scores combining both BLISS studies showed that clinical improvement with belimumab treatment was most evident in musculoskeletal and mucocutaneous domains. Less worsening of disease activity with belimumab therapy was seen in hematologic, immunological, and renal domains.86 Another pooled post hoc analysis was performed of the BLISS studies to determine the effect of belimumab on patients with renal involvement and showed that those receiving MMF, or those with serologic activity at baseline, had a greater improvement in renal disease with belimumab than with placebo.87 In a further post hoc analysis of the BLISS trials, greater clinical efficacy with belimumab was seen in SLE patients who were serologically more active and had higher clinical disease activity as defined as SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment) (Systemic Lupus Erythematosus Disease Activity Index) >10.88

On the basis of the BLISS clinical trial results, the US Food and Drug Administration and the European Medicines Agency approved belimumab (10 mg/kg) for use in addition to standard of care in autoantibody positive SLE patients with moderate-to-severe disease activity, with the exception of those with active lupus nephritis or neuropsychiatric lupus.

Safety and tolerability data following 7 years of belimumab patient exposure have been published showing that the most common adverse events reported were mild-to-moderate infections particularly upper respiratory tract infections.89 One case of progressive multifocal leuco-encephalopathy has been reported to date in a belimumab-treated SLE patient.90

Therapies targeting T-B lymphocyte interactions with abatacept

Immunological tolerance may be induced by the blockade of costimulatory interactions between T- and B-cells. CD28 is a T-cell costimulatory ligand that interacts with the receptors B7-1 (CD80) and B7-2 (CD86). CTLA4 on activated T-cells interacts with B7 with greater affinity than CD28 resulting in a negative feedback loop that inhibits T-cell activation.9597 Abatacept is a fusion protein comprised of CTLA-4 (cytotoxic T-lymphocyte antigen) combined with the Fc portion of human IgG1 (CTLA-4-Ig). CTLA-4-Ig has been shown to slow progression of lupus nephritis in murine models of disease.98100 Clinical trials of abatacept in SLE are summarized in Table 2.

Table 2 Non-B-cell targeted biologic therapies in SLE
Note: Information regarding ongoing clinical trials in SLE obtained from ClinicalTrials.gov.
Abbreviations: CYCLO, cyclophosphamide; IFN, interferon; Ig, immunoglobulin; IL, interleukin; mRNA, messenger RNA; SLE, systemic lupus erythematosus.

Targeting type I interferon in SLE

The type I interferon family plays a key role in innate immunity and host viral defense. It is well established that SLE patients have high serum levels of interferon-α which correlate with disease activity.104106 In addition, SLE patients have an interferon gene expression signature in peripheral blood mononuclear cells, particularly in the early stages of their disease course.107,108 A number of anti-interferon-α therapies have been investigated in SLE patients with promising results and these clinical studies are outlined in Table 2. It should be noted that to date the main finding in SLE patients treated with anti-interferon-α therapies has been a decrease in the interferon gene expression signature and clinical response to these agents has yet to be fully determined. Phase III studies are now planned to investigate this further.

Adjunctive therapies in SLE

While immunosuppressive and biologic agents are the cornerstone of inflammatory disease management in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected.

The role of antimalarials in SLE

Hydroxychloroquine, while most ostensibly used in the symptomatic treatment of musculoskeletal and cutaneous features of SLE, has a plethora of unseen beneficial effects. Low serum levels of hydroxychloroquine, suggesting poor medication adherence, have been found to be predictive of disease flares in SLE patients.123 Furthermore, SLE patients with quiescent disease who are taking hydroxychloroquine are less likely to have a clinical flare if they are maintained on the drug.124 Hydroxychloroquine usage is associated with a reduced risk of damage accrual in SLE patients and has a protective effect on renal damage.125,126 In addition, hydroxychloroquine has been shown to have a beneficial effect on patient survival.127

Hydroxychloroquine has been shown to have a positive effect on lipid profiles in SLE patients with significant reductions in total cholesterol, low density lipoprotein, and triglycerides and significant increases in high density lipoprotein levels.128130 Hydroxychloroquine may also play a role in reducing cardiovascular and thrombotic risk in SLE patients.131133 Both current and past use of hydroxychloroquine have been associated with a beneficial effect on bone mineral density, with higher mean bone mineral density of the spine and the hip.134,135

Patients receiving hydroxychloroquine are at risk of developing retinopathy. While this complication is rare, it is recommended that patients have a baseline eye visual field examination. Thereafter, in low risk patients, no further testing is required for the next 5 years. After the first 5 years of therapy, an annual eye examination is recommended. In high risk patients, those with macular degeneration, retinal dystrophy, or greater than 5 year’s duration of hydroxychloroquine therapy, yearly eye examinations are recommended.136 Patients with severe renal or hepatic impairment are at greater risk of toxicity related to hydroxychloroquine due to reduced clearance of the drug and dose adjustment should be considered in such individuals.

Managing cardiovascular risk in SLE

Atherosclerosis has become a leading cause of morbidity and mortality in SLE patients. The risk of cerebrovascular and coronary heart disease-related events is 5–10 times higher in those with SLE as compared to the normal population.137140 SLE patients are known to have an increased prevalence of cardiovascular risk factors such as hypertension and dyslipidemia, and often tend to have a sedentary lifestyle.137142 Furthermore, SLE patients frequently receive corticosteroid therapy which may exacerbate their cardiovascular risk factors. In addition to an excess of traditional risk factors, it has been established that SLE patients have an inherent increased risk of cardiovascular disease and premature atherosclerosis.143145

Cardiovascular risk factors in SLE patients should ideally be assessed at baseline and during follow-up on an annual basis and should include a smoking assessment, review of vascular events (cerebral/cardiovascular), and levels of physical activity, and family history of cardiovascular disease. Lipid profile, glucose, and blood pressure should be monitored and treated accordingly. All patients with SLE should have antiphospholipid antibody markers measured at diagnosis and confirmatory testing at least 12 weeks later performed if the baseline tests are positive. Those on long-term corticosteroids may require more frequent monitoring.146

Minimizing infection risk in SLE

Patients with SLE are at high risk of infections both as a consequence of their disease and the infection therapies used in their clinical management. The administration of inactivated vaccines, particularly the inactivated influenza vaccine and the 23-valent polysaccharide pneumococcal vaccine, is strongly encouraged in SLE patients on immunosuppression. Vaccines should ideally be given before commencing B-cell depleting therapy such as rituximab, or at least 6 months after the start of therapy but 4 weeks before the next course. Live attenuated vaccines should be avoided in immunosuppressed patients.147

Bone health in SLE

The prevalence of osteoporosis in SLE varies from 4% to 24% and vertebral fracture prevalence ranges between 7.6% and 37%.148,149 Several factors may contribute to reduced bone mineral density in a patient with SLE including persistently active disease and chronic inflammation, reduced physical activity, vitamin D deficiency, ovarian failure, and renal failure.150 With this in mind, all patients with SLE should be assessed for adequate calcium and vitamin D intake and supplemented if necessary. Existing guidelines for the treatment and prevention of osteoporosis should be followed for postmenopausal women and those on corticosteroids.

Conclusion

The management of SLE has progressed enormously in the last 10 years and we are now in the era of biologic therapies for this complex disease. While there are currently two such agents available in some developed countries (belimumab and rituximab), intensive efforts are underway to develop further biologic therapies to address a major unmet need in patients refractory to conventional therapies. Funding for these therapies remains a major limitation to availability for patients. For example, while belimumab is widely used in North America, its use has been limited on the grounds of cost-effectiveness in many European countries.

The indications for the use of B-cell depletion therapies remain uncertain and they are currently used in patients with very active disease who have failed one or more immunosuppressive therapies. However, as in rheumatoid arthritis, there may be a case for introducing biologic therapies very early in the disease course to prevent disease progression and damage accumulation. Selecting appropriate patients for biologic therapies is very challenging and, unless done accurately, risks over treating patients who could have responded well to conventional approaches.

Designing and delivering clinical trials in SLE remains exceptionally challenging given the complexity of the disease, the variability of clinical features between patients, and the high usage of concomitant corticosteroids and effective immunosuppressive therapies. Other challenges include defining outcome measures for clinical trials – the choice of outcome can make or break a clinical trial as demonstrated in lupus nephritis.102,103 There have been ~20 industry led trials of 16 molecules in patients with SLE, with only two successful studies (BLISS-52 and BLISS-76). Nevertheless, several ongoing studies have been outlined in this review with some grounds for cautious optimism.

Biosimilar monoclonal antibodies are becoming available. The US patent for rituximab expires in 2016 and the European patent expired in 2013. There are at least 20 pharmaceutical companies investigating rituximab biosimilars in rheumatoid arthritis and lymphoma and many of these studies are direct comparisons with MabThera/Rituxan branded rituximab. To our knowledge, there are no studies of biosimilar rituximab molecules in SLE.

Overreliance on corticosteroid therapy remains an important issue in the management of SLE and contributes significantly to cardiovascular risk, long-term damage accrual, and mortality.151 A recent prospective observational study of rituximab as part of a corticosteroid sparing regimen in lupus nephritis patients has shown encouraging results.70 The RITUXILUP multicenter randomized controlled trial of rituximab and MMF with limited corticosteroid for the treatment of lupus nephritis is ongoing.

Hydroxychloroquine use remains the first-line agent in the treatment of SLE and evidence continues to accumulate attesting to its benefits in improving morbidity and mortality. Equally important is the fundamental need for each patient to participate in a chronic disease management program to minimize comorbidities such as infection, cardiovascular risks, bone health, and the detection and early management of disease flares to limit damage accumulation.

Disclosure

D D’Cruz reports participation in advisory boards and consultancies for Human Genome Sciences and Roche and has received consulting fees and/or has participated in clinical trials for GlaxoSmithKline, Bristol Myers Squibb, TEVA, Merck Serono, and Eli-Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the paper apart from those disclosed.


References

1.

Merrell M, Shulman LE. Determination of prognosis in chronic disease, illustrated by systemic lupus erythematosus. J Chronic Dis. 1955; 1(1):12–32.

2.

Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2550–2557.

3.

Bruce IN, O’Keeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis. 2015;74(9):1706–1713.

4.

Moroni G, Quaglini S, Maccario M, Banfi G, Ponticelli C. “Nephritic flares” are predictors of bad long-term renal outcome in lupus nephritis. Kidney Int. 1996;50(6):2047–2053.

5.

Danila MI, Pons-Estel GJ, Zhang J, Vilá LM, Reveille JD, Alarcón GS. Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort. Rheumatology (Oxford). 2009;48(5):542–545.

6.

Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012;71(11):1771–1782.

7.

Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res. (Hoboken). 2012;64(6):797–808.

8.

Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–1112.

9.

Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. 2005;16:1076–1084.

10.

Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353(21):2219–2228.

11.

Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford). 2010;49(1):128–140.

12.

Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51(4):1188–1195.

13.

Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350(10):971–980.

14.

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. 2010; 69(1):61–64.

15.

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. 2002;46(8):2121–2131.

16.

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. 2010;69(12):2083–2089.

17.

Mok CC, Ho CT, Chan KW, Lau CS, Wong RW. Outcome and prognostic indicators of diffuse proliferative lupus glomerulonephritis treated with sequential oral cyclophosphamide and azathioprine. Arthritis Rheum. 2002;46(4):1003–1013.

18.

Wofsy D, Appel GB, Dooley MA, et al. Group AS. Aspreva Lupus Management Study (ALMS): maintenance results. Arthritis Rheum. 2010;62(Suppl 10):2085.

19.

Dooley MA, Jayne D, Ginzler EM, et al; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365:1886–1895.

20.

Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet. 2012; 158(3):588–596.

21.

Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162(1):18–26.

22.

Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis. Epub 2014 Dec 30.

23.

Yap DY, Ma MK, Mok MM, et al. Long-term data on tacrolimus treatment in lupus nephritis. Rheumatology (Oxford). 2014; 53(12):2232–2237.

24.

Webster P, Wardle A, Bramham K, Webster L, Nelson-Piercy C, Lightstone L. Tacrolimus is an effective treatment for lupus nephritis in pregnancy. Lupus. 2014;23(11):1192–1196.

25.

Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010;69(12):2074–2082.

26.

Trevisani VF, Castro AA, Neves Neto JF, Atallah AN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2006;(2):CD002265.

27.

Trevisani VF, Castro AA, Neves Neto JF, Atallah AN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2013;2:CD002265.

28.

Neuwelt CM, Lacks S, Kaye BR, Ellman JB, Borenstein DG. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med. 1995;98(1):32–41.

29.

Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(4):620–625.

30.

Leung FK, Fortin PR. Intravenous cyclophosphamide and high dose corticosteroids improve MRI lesions in demyelinating syndrome in systemic lupus erythematosus. J Rheumatol. 2003;30(8):1871–1873.

31.

McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med. 1988;318(22):1423–1431.

32.

Ramos PC, Mendez MJ, Ames PR, Khamashta MA, Hughes GR. Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol. 1996;14(3):295–299.

33.

Mok CC, Lau CS, Wong RW. Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study. Am J Med. 2003;115(1):59–62.

34.

Tomietto P, D’Agostini S, Annese V, De Vita S, Ferraccioli G. Mycophenolate mofetil and intravenous dexamethasone in the treatment of persistent lupus myelitis. J Rheumatol. 2007;34(3):588–591.

35.

Riskalla MM, Somers EC, Fatica RA, McCune WJ. Tolerability of mycophenolate mofetil in patients with systemic lupus erythematosus. J Rheumatol. 2003;30(7):1508–1512.

36.

Carneiro JR, Sato EI. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol. 1999;26(6):1275–1279.

37.

Islam MN, Hossain M, Haq SA, Alam MN, Ten Klooster PM, Rasker JJ. Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus. Int J Rheum Dis. 2012;15(1):62–68.

38.

Rahman P, Humphrey-Murto S, Gladman DD, Urowitz MB. Efficacy and tolerability of methotrexate in antimalarial resistant lupus arthritis. J Rheumatol. 1998;25(2):243–246.

39.

Winzer M, Aringer M. Use of methotrexate in patients with systemic lupus erythematosus and primary Sjogren’s syndrome. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S156–S159.

40.

Remer CF, Weisman MH, Wallace DJ. Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study. Lupus. 2001;10(7):480–483.

41.

Wu GC, Xu XD, Huang Q, Wu H. Leflunomide: friend or foe for systemic lupus erythematosus? Rheumatol Int. 2013;33(2):273–276.

42.

Distad BJ, Amato AA, Weiss MD. Inflammatory myopathies. Curr Treat Options Neurol. 2011;13(2):119–130.

43.

Pisoni CN, Cuadrado MJ, Khamashta MA, Hughes GR, D’Cruz DP. Mycophenolate mofetil treatment in resistant myositis. Rheumatology (Oxford). 2007;46(3):516–518.

44.

Majithia V, Harisdangkul V. Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune inflammatory myopathy. Rheumatology (Oxford). 2005;44(3):386–389.

45.

Kono DH, Klashman DJ, Gilbert RC. Successful IV pulse cyclophosphamide in refractory PM in 3 patients with SLE. J Rheumatol. 1990; 17(7):982–983.

46.

Kuhn A, Specker C, Ruzicka T, Lehmann P. Methotrexate treatment for refractory subacute cutaneous lupus erythematosus. J Am Acad Dermatol. 2002;46(4):600–603.

47.

Bohm L, Uerlich M, Bauer R. Rapid improvement of subacute cutaneous lupus erythematosus with low-dose methotrexate. Dermatology. 1997; 194(3):307–308.

48.

Wenzel J, Brahler S, Bauer R, Bieber T, Tüting T. Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol. 2005;153(1):157–162.

49.

Malcangi G, Brandozzi G, Giangiacomi M, Zampetti M, Danieli MG. Bullous SLE: response to methotrexate and relationship with disease activity. Lupus. 2003;12(1):63–66.

50.

Callen JP, Spencer LV, Burruss JB, Holtman J. Azathioprine. An effective, corticosteroid-sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vasculitis. Arch Dermatol. 1991;127(4):515–522.

51.

Shehade S. Successful treatment of generalized discoid skin lesions with azathioprine. Arch Dermatol. 1986;122(4):376–377.

52.

Kreuter A, Tomi NS, Weiner SM, Huger M, Altmeyer P, Gambichler T. Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy. Br J Dermatol. 2007; 156(6):1321–1327.

53.

Schanz S, Ulmer A, Rassner G, Fierlbeck G. Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil. Br J Dermatol. 2002;147(1):174–178.

54.

Gammon B, Hansen C, Costner MI. Efficacy of mycophenolate mofetil in antimalarial-resistant cutaneous lupus erythematosus. J Am Acad Dermatol. 2011;65(4):717–721.

55.

Chang AY, Werth VP. Treatment of cutaneous lupus. Curr Rheumatol Rep. 2011;13(4):300–307.

56.

Chen M, Doherty SD, Hsu S. Innovative uses of thalidomide. Dermatol Clin. 2010;28(3):577–586.

57.

Abu-Shakra M, Shoenfeld Y. Azathioprine therapy for patients with systemic lupus erythematosus. Lupus. 2001;10(3):152–153.

58.

Mok CC. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol. 2007;36(5):329–337.

59.

Boumpas DT, Barez S, Klippel JH, Barlow JE. Intermittent cyclophosphamide for the treatment of autoimmune thrombocytopenia in systemic lupus erythematosus. Ann Intern Med. 1990;112(9):674–677.

60.

Walport MJ, Hubbard WN, Hughes GR. Reversal of aplastic anaemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide. Br Med J. 1982;285(6344):769–770.

61.

Levy Y, Sherer Y, Ahmed A, et al. study of 20 SLE patients with intravenous immunoglobulin – clinical and serologic response. Lupus. 1999;8(9):705–712.

62.

Maier WP, Gordon DS, Howard RF, et al. Intravenous immunoglobulin therapy in systemic lupus erythematosus-associated thrombocytopenia. Arthritis Rheum. 1990;33(8):1233–1239.

63.

Lu TY, Ng KP, Cambridge G, et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum. 2009;61(4):482–487.

64.

Terrier B, Amoura Z, Ravaud P, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010;62(8):2458–2466.

65.

Catapano F, Chaudhry AN, Jones RB, Smith KG, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25(11):3586–3592.

66.

Diaz-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. 2012;11(5):357–364.

67.

Pepper R, Griffith M, Kirwan C, et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant. 2009;24(12):3717–3723.

68.

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. 2010;62(1):222–233.

69.

Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012; 64(4):1215–1226.

70.

Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280–1286.

71.

Diaz-Lagares C, Perez-Alvarez R, Garcia-Hernandez FJ, et al. Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label. Arthritis Res Ther. 2011;13(4):R112.

72.

Calabrese LH, Molloy ES. Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies. Ann Rheum Dis. 2008;67(Suppl 3):64–65.

73.

Jacobi AM, Goldenberg DM, Hiepe F, Radbruch A, Burmester GR, Dörner T. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis. 2008;67(4):450–457.

74.

Dorner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther. 2006;8(3):R74.

75.

Wallace DJ, Gordon C, Strand V, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology (Oxford). 2013;52(7):1313–1322.

76.

Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis. 2014;73(1):183–190.

77.

Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999; 285(5425):260–263.

78.

Schneider P, Mackay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189(11):1747–1756.

79.

Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404(6781):995–999.

80.

Thompson JS, Bixler SA, Qian F, et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science. 2001; 293(5537):2108–2111.

81.

Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44(6):1313–1319.

82.

Petri M, Stohl W, Chatham W, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58(8):2453–2459.

83.

Collins CE, Gavin AL, Migone TS, Hilbert DM, Nemazee D, Stohl W. B lymphocyte stimulator (BLyS) isoforms in systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mRNA levels than with plasma BLyS protein levels. Arthritis Res Ther. 2006;8(1):R6.

84.

Navarra SV, Guzman 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. 2011; 377(9767):721–731.

85.

Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918–3930.

86.

Manzi S, Sánchez-Guerrero J, Merrill JT, et al. BLISS-52 and BLISS-76 Study Groups. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012;71(11):1833–1838.

87.

Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63–72.

88.

Van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343–1349.

89.

Ginzler EM, Wallace DJ, Merrill JT, et al; LBSL02/99 Study Group. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol. 2014;41(2):300–309.

90.

Fredericks C, Kvam K, Bear J, Crabtree GS, Josephson SA. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus. 2014;23(7):711–713.

91.

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.

92.

Dall’era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 2007;56(12):4142–4150.

93.

Ginzler EM, Wax S, Rajeswaran A, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther. 2012;14(1):R33.

94.

Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015;74:2006–2015.

95.

Scheipers P, Reiser H. Role of the CTLA-4 receptor in T cell activation and immunity. Physiologic function of the CTLA-4 receptor. Immunol Res. 1998;18(2):103–115.

96.

Reiser H, Stadecker MJ. Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases. N Engl J Med. 1996; 335(18):1369–1377.

97.

Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily-CTLA-4. Nature. 1987;328(6127):267–270.

98.

Daikh DI, Wofsy D. Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. J Immunol. 2001; 166(5):2913–2916.

99.

Cunnane G, Chan OT, Cassafer G, et al. Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum. 2004;50(5):1539–1548.

100.

Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science. 1994;265(5176):1225–1227.

101.

Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(10):3077–3087.

102.

Furie R, Nicholls K, Cheng TT, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 2014;66(2):379–389.

103.

Wofsy D, Hillson P, Diamond B. Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials. Arthritis Rheum. 2013;65(6):1586–1591.

104.

Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979;301(1):5–8.

105.

Ytterberg SR, Schnitzer TJ. Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 1982;25(4):401–406.

106.

Bengtsson AA, Sturfelt G, Truedsson L, et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus. 2000;9(9):664–671.

107.

Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6):711–723.

108.

Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610–2615.

109.

Merrill JT, Wallace DJ, Petri M, et al. Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis. 2011;70(11):1905–1913.

110.

Petri M, Wallace DJ, Spindler A, et al. Sifalimumab, a human anti- interferon-alpha monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum. 2013;65(4):1011–1021.

111.

Khamashta M, Merrill JT, Werth VP, et al. Safety and efficacy of sifalimumab, an anti IFN-alpha monoclonal antibody, in a phase 2b study of moderate to severe systemic lupus erythematosus (SLE). Arthritis Rheum. 2014;66(Suppl):L4 (Late Breaking Abstract).

112.

McBride JM, Jiang J, Abbas AR, et al. Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis Rheum. 2012;64(11):3666–3676.

113.

Peng L, Oganesyan V, Wu H, Dall’Acqua WF, Damschroder MM. Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-α receptor 1 antibody. MAbs. 2015;7(2):428–439.

114.

Morehouse C, Chang L, Wang et al. Target modulation of a type I interferon (IFN) gene signature with sifalimumab or anifrolumab in systemic lupus erythematosus (SLE) patients in two open label phase 2 Japanese trials. 2014 ACR/ARHP Annual Meeting; November 14–19; 2014; Boston, MA.

115.

Ryffel B, Car BD, Gunn H, Roman D, Hiestand P, Mihatsch MJ. Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am J Pathol. 1994;144(5):927–937.

116.

Yang G, Liu H, Jiang M, et al. Experimental study on intramuscular injection of eukaryotic expression vector pcDNA3-IL-6 on BXSB mice. Chin Med J. 1998;111(1):38–42.

117.

Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology. 2006;119(3):296–305.

118.

Mihara M, Takagi N, Takeda Y, Ohsugi Y. IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol. 1998;112(3):397–402.

119.

Chun HY, Chung JW, Kim HA, et al. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol. 2007;27(5):461–466.

120.

Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol. 1991;147(1):117–123.

121.

Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010;62(2):542–552.

122.

Shirota Y, Yarboro C, Fischer R, Pham TH, Lipsky P, Illei GG. Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis. 2013;72(1):118–128.

123.

Costedoat-Chalumeau N, Amoura Z, Hulot J, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(10):3284–3290.

124.

The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulphate in systemic lupus erythematosus. N Engl J Med. 1991;324(3):150–154.

125.

Fessler BJ, Alarcón GS, McGwin G Jr, et al; LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005;52(5):1473–1480.

126.

Pons-Estel GJ, Alarcón GS, McGwin G, et al; Lumina Study Group. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009;61(6):830–839.

127.

Alarcon G, McGwin G, Bertoli A, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66(9):1168–1172.

128.

Borba EF, Bonfá E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J Rheumatol. 2001;28(4):780–785.

129.

Tam L, Gladman D, Hallett D, Rahman P, Urowitz MB. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol. 2000;27(9):2142–2145.

130.

Rahman P, Gladman D, Urowitz M, Yuen K, Hallett D, Bruce IN. The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol. 1999; 26(2):325–330.

131.

Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med. 1994;96(3):254–259.

132.

Ruiz-Irastorza G, Egurbide M, Pijoan J, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15(9):577–583.

133.

Erkan D, Yazici Y, Peterson M, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford). 2002;41(8):924–929.

134.

Mok C, Mak A, Ma K. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus. 2005; 14(2):106–112.

135.

Lakshminarayanan S, Walsh S, Mohanraj M, Rothfield N. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol. 2001;28(1):102–108.

136.

Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF; American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002;109(7):1377–1382.

137.

Bruce IN, Gladman DD, Urowitz MB. Premature atherosclerosis in SLE. Rheum Dis Clin North Am. 2000;26(2):257–278.

138.

Salmon JE, Roman MJ. Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. Curr Opin Rheumatol. 2001;13(5):341–344.

139.

Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study. Am J Epidemiol. 1997;145(5):408–415.

140.

Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum. 1999;42(2):338–346.

141.

Calvo-Alén J, Toloza SM, Fernández M, et al. LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005;52(7):2060–2068.

142.

Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349(25):2407–2415.

143.

Bruce IN, Urowitz MB, Gladman DD, Ibañez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum. 2003;48(11):3159–3167.

144.

Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001; 44(10):2331–2337.

145.

Manzi S, Selzer F, Sutton-Tyrrell K, et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum. 1999;42(1):51–60.

146.

Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematosus – proposed guidelines for risk factor management. Rheumatology (Oxford). 2004;43(1):7–12.

147.

Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis. 2010;69(7):1269–1274.

148.

Almehed K, Forsblad d’Elia H, Kvist G, Ohlsson C, Carlsten H. Prevalence and risk factors of osteoporosis in female SLE patients-extended report. Rheumatology (Oxford). 2007;46(7):1185–1190.

149.

Bultink IE, Lems WF, Kostense PJ, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52(7):2044–2050.

150.

Mak A, Lim JQ, Liu Y, Cheak AA, Ho RC. Significantly higher estimated 10-year probability of fracture in lupus patients with bone mineral density comparable to that of healthy individuals. Rheumatol Int. 2013;33(2):299–307.

151.

Bruce I, O’Keeffe A, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis. 2015;74(9):1706–1713.

152.

Isenberg DA, Petri M, Kalunian K, et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2015 [Epub ahead of print].

153.

Merrill JT, van Vollenhoven RF, Buyon JP, et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2015 [Epub ahead of print].

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.