Optimising management of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder that predominantly affects women of child-bearing age with a ~9:1 female-to-male ratio. Patients with SLE suffer an impaired health-related quality of life (HRQoL), and experience fatigue and pain as major problems. 

 

The pathogenesis of SLE is multifactorial and its aetiology is largely unknown.¹ Genes, hormones and environmental factors have been implicated among the causes of the disease. Multiple organs may be involved, including the skin, joints, kidneys and the central nervous system, with renal and neuropsychiatric SLE probably constituting the most severe manifestations. Considerable variations in severity can be observed during the course of the disease, with periods of remission and flares, the intensity of the latter ranging from mild to severe, to sometimes organ- or life-threatening. Mortality during the early course of the disease is associated with activity grade and infections, but comorbidities, especially cardiovascular disease, are considerable causes of death at later stages.²

 

In SLE, both the innate and the adaptive immunity may be aberrant, and defective apoptotic cell clearance is hypothesised to be a central phenomenon underlying the initiation of autoreactive responses. The type I interferon pathway has a central role in the pathogenesis of SLE,³ and the hyperactivity of the B cell lineage also has pivotal significance. The disease is characterised by a prominent production of autoantibodies to nuclear components and immune complex depositions, resulting in inflammation and damage in organs and/or tissues. There is now a better understanding of autoimmunity in SLE, which has led to improved therapeutic strategies, but revolutionary treatments have yet to be discovered. 

 

The management of SLE and the development of new therapies have been challenging because of the prominent heterogeneity of the disease in clinical presentation and underlying immunopathology, as well as its unpredictable course. For these reasons, the treatment of SLE varies and is highly individualised. Commonly used therapies include corticosteroids, antimalarial agents, immunosuppressive agents and non-steroidal anti-inflammatory drugs (NSAIDs).^4,5 Several immune components have been identified as potential targets of novel treatments. Unfortunately, the majority of trials have failed. In 2011, drug agencies in several countries approved belimumab, an anti-BAFF (B cell-activating factor belonging to the TNF family) monoclonal antibody, for the treatment of SLE.^6,7 The introduction of belimumab has contributed to improved management; however, it is still unclear which patient groups are expected to benefit most from this drug. Considering the cost and potential toxicity of biologic therapies, further survey towards identification of predictors of treatment response is of utmost importance.

 

The management of SLE has traditionally been non-specific, with symptomatic therapeutic approaches. As mentioned above, the reasons for this can be traced to: (i) the lack of therapies targeting specific immune components, with the possible exceptions of belimumab, rituximab and cyclosporine; and (ii), the wide spectrum of clinical manifestations. The treatment strategies are therefore individual, depending on the organ involvement, the severity of the disease and the complications. Non-major organ involvement may be treated with for example, glucocorticoids, antimalarial agents, and NSAIDs. In more severe or non-responsive cases, azathioprine, mycophenolate mofetil and methotrexate are commonly used. Despite their widespread use, not all of these drugs have been approved for SLE.

 

The use of antimalarial agents in SLE is coupled to a wide variety of beneficial effects, making this drug class the cornerstone of SLE therapy.^8,9 The modulatory effects of antimalarial agents on immune responses are mediated by several mechanisms, for example, through interference with antigen processing. The use of antimalarial agents in SLE has been associated with remission maintenance effects,⁸ as well as prevention of flares and decreased corticosteroid use during pregnancy.¹⁰ Hydroxychloroquine 

has been shown to improve renal prognosis in patients with lupus nephritis.¹¹ Based on their atheroprotective effects, antimalarial agents are expected to be beneficial in SLE patients at high risk for thrombotic events; for example, patients with the antiphospholipid syndrome or high titres of antiphospholipid antibodies. It is recommended that all SLE patients receive adequate doses of antimalarial agents unless it is contraindicated due to, for example, retinopathy. 

 

Glucocorticoids have rapid and powerful anti-inflammatory and immunosuppressive effects,¹² and are used for most SLE manifestations, from mild cutaneous disease to life-threatening conditions, often in combination with other drugs. Pulse methylprednisolone therapy is commonly used during severe exacerbations to induce remission, followed by high doses of oral corticosteroids with a gradual taper. Low-dose oral corticosteroids are used in the vast majority of SLE patients as a long-term remission maintenance therapy. Fortunately, the glucocorticoid-induced harm has received increasing recognition in recent years. 

 

Apart from complications, recent indications of harmful effects of glucocorticoids on SLE itself have contributed to a scepticism towards the acceptance of long-term use, and a need for a paradigm shift has emerged.¹³

 

Moderate to severe flares in major organs are usually managed with an initial induction therapy using methylprednisolone, cyclophosphamide, mycophenolate mofetil, or combinations thereof.^14–16 In lupus nephritis, the low-dose regimen proposed in the Euro-Lupus Nephritis Trial¹⁷ is the most commonly used cyclophosphamide regimen, and comprises six pulses of 0.5g cyclophosphamide, one every second week for a total of three months, followed by maintenance therapy with azathioprine. Together with mycophenolate mofetil, this regimen has replaced the initial high dose NIH cyclophosphamide protocol,^18–20 mainly because of severe infections and toxicity concerns, for example, associations with premature gonadal failure.²¹ In patients with nephritis who have not responded to this management, the anti-CD20 monoclonal antibody rituximab may be an alternative.²²

 

Calcineurin inhibitors have received growing attention as potential therapeutic agents in SLE, especially in lupus nephritis.²³ Low doses of tacrolimus are effective and well tolerated in patients with renal SLE who have failed treatment with cyclophosphamide,24 and an open-label prospective study showed non-inferiority of tacrolimus as an induction therapy of active biopsy-proven nephritis compared with mycophenolate mofetil and cyclophosphamide.²⁵ Later, a meta-analysis of nine studies demonstrated that tacrolimus was superior to cyclophosphamide but not to mycophenolate mofetil in inducing complete renal remission in lupus nephritis.²⁶ Results from recent studies of voclosporine are awaited.

 

In recent years, more targeted therapies have been investigated, and biological agents have been used either following approval or as off-label therapies. Future strategies that may prove promising include small molecules modifying intracellular signal pathways, for example, through targeting Lyn, Syk, PI3Ks and Btk. The proteasome inhibitor bortezomib, approved for the treatment of multiple myeloma, was recently shown to improve the disease activity and reduce the numbers of peripheral blood and bone marrow plasma cells in twelve refractory SLE patients.²⁷

 

Lupuzor, also known as P140 peptide and IPP-201101, is a 21-mer linear peptide originating from the small nuclear ribonucleoprotein U1-70K, phosphorylated at the Ser140 position. The mechanism of action of lupuzor is not fully elucidated, but studies in lupus-prone mice have shown promising immunomodulatory effects,^28–33 and a Phase IIb trial evaluating 149 SLE patients documented greater response rates in patients receiving lupuzor than in patients receiving placebo.³⁴

 

Biologic agents have been the focus of research towards the development of modern therapies. Due to its important role in B cell homeostasis, BAFF has been of central interest as a target molecule. Belimumab is the first drug to be licensed for use in SLE in more than 50 years, and the first biologic agent approved for the disease. 

 

The efficacy of belimumab in reducing SLE activity has been shown in Phase III randomised placebo-controlled clinical trials.^35,36 Belimumab is a recombinant human IgG1-λ monoclonal antibody that specifically binds to the soluble BAFF fragment, and prevents the binding of BAFF to its receptors on the surface of B cells. Normally, the binding of BAFF to B cells prolongs their survival and promotes their maturation and differentiation towards immunoglobulin production.37 BAFF signalling also leads to increases in anti-apoptotic proteins. As defective clearance of apoptotic cells is implicated in the pathogenesis of SLE and the stimulation of autoantibody production, the reductions in anti-apoptotic proteins as a result of BAFF inhibition is expected to hamper this B cell-driven component in the pathogenesis of the disease. 

 

Rituximab is a chimeric anti-CD20 monoclonal antibody, widely used for the treatment of non-Hodgkin lymphoma, rheumatoid arthritis, vasculitis and other autoimmune diseases, and also as an off-label therapy in refractory SLE, mostly for therapy-resistant lupus nephritis.^38,39

 

Several centres have reported uncontrolled experiences with rituximab for the treatment of severe and refractory SLE, including cohorts of lupus nephritis.^22,40–50 Studies of refractory renal SLE treated with rituximab combined with cyclophosphamide reported beneficial effects on various outcomes.^{22,41,42,51–53} However, randomised controlled trials of rituximab treatment in patients with SLE failed to show efficacy.^54,55 Despite the negative results of the clinical trials, rituximab has been included in European and American recommendations for the management of renal SLE.^56,57 Apart from refractory renal SLE, the use of rituximab has also been documented in other organ manifestations, such as severe arthritis, haematological abnormalities, and neuropsychiatric SLE when conventional treatments have failed.^38,58–60

 

Atacicept, another biologic agent, which blocks the effects of both BAFF and its homologous molecule APRIL (a proliferation-inducing ligand),⁶¹ has also been studied as a candidate drug for SLE. A clinical trial of atacicept in lupus nephritis was terminated prematurely, due to adverse events, that is, hypogammaglobulinaemia and infections.⁶² Blisibimod is a fusion protein consisting of four high-affinity BAFF-binding domains and the Fc domain of human IgG1, targeting both soluble and membrane-bound BAFF. A dose-ranging Phase IIb clinical trial of blisibimob⁶³ determined a safe and effective dose to further be studied in a Phase III trial, which unfortunately was not successful.

 

 Only one of the two Phase III trials of tabalumab, a fully human monoclonal antibody targeting soluble and membrane-bound BAFF, met its primary endpoint,^64,65 being the reason why no further development of the drug was planned for SLE. However, no dose-ranging Phase II studies had preceded the Phase III trials, and several outcomes in both trials justify the rationale of targeting BAFF in SLE.^66,67

 

Phase II68 and Phase IIb69 clinical trials of epratuzumab, a humanised monoclonal antibody against CD22, demonstrated favourable effects on SLE disease activity, prompting the initiation of two Phase III trials, which unfortunately failed to meet their primary clinical efficacy endpoints.⁷⁰ Experimental inhibition of IL-6 in murine lupus impedes autoreactive B cell activity and ameliorate nephritis features,^71,72 but a proof-of-concept study of the human anti-IL-6 monoclonal antibody sirukumab failed to demonstrate superiority of the drug to placebo in patients with active nephritis.⁷³ A Phase I trial of the IL-6 receptor antagonist tocilizumab showed improved SLE disease activity and decreased autoantibody production, but the observed dose-related decreases in absolute neutrophil counts raised concerns.⁷⁴

 

The importance of the type I IFN pathway in the pathogenesis of SLE has prompted the investigation of anti-IFN antibodies as potential drugs.⁷⁵ The first data supporting the efficacy of IFN-α inhibition came from a Phase IIb trial of sifalimumab;⁷⁶ the results were modest but in favour of sifalimumab. However, another phase II study of the monoclonal anti-IFN-α antibody rontalizumab demonstrated superiority to placebo in patients with low IFN-regulated gene expression, but not in patients with high IFN gene signature,⁷⁷ contrary to what was expected considering the biologic mechanism of the drug. A Phase II trial of the type I IFN receptor antagonist anifrolumab has been successful, meriting further development of this agent. Anifrolumab was more efficacious than placebo, especially in patients with a high IFN gene signature; however, no dose response was displayed.⁷⁸ Results from ongoing trials, including a trial in lupus nephritis, are awaited. 

 

Abatacept, a soluble fusion protein comprising the extracellular domain of the human cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and a fragment of the Fc portion of human IgG1, has also been investigated as a potential treatment for SLE. T cell activation relies on co-stimulatory interactions. The interaction of CD80/86 on antigen-presenting cells with CD28 on T cells is one of the most important co-stimulatory pathways. The CLTA-4 molecule is homologous to CD28, but binds to CD80 and CD86 with higher affinity, resulting in competitive inhibition of the binding of CD28 to CD80/CD86. Abatacept is approved for use in rheumatoid arthritis and has also been studied in other autoimmune diseases.

 

Two randomised clinical trials in SLE patients have been conducted. Patients with a current mucocutaneous, musculoskeletal or serositis flare were included in the first trial;⁷⁹ unfortunately, abatacept did not prove more efficient than placebo. Later discussions raised the concern whether the choice of the primary endpoint in this trial concealed the inferiority of abatacept to placebo.⁸⁰ The second trial of abatacept in SLE was a Phase II/III trial comprising 298 patients with active biopsy-proven proliferative lupus nephritis.⁸¹ The patients were randomised to receive abatacept or placebo in addition to glucocorticoids and mycophenolate mofetil. The time to attain complete response did not differ between the treatment arms, but greater improvements were seen in favour of abatacept regarding serologic markers and proteinuria. Later, a reanalysis with different definitions of renal response unveiled inferiority of abatacept to placebo,⁸² highlighting that the choice of outcomes in clinical trials might be determinant of their success. 

 

The heterogeneity of SLE makes the design of clinical trials and the choice of adequate outcome measures challenging. Moreover, sufficient numbers of SLE patients in clinical trials can only be guaranteed by joint efforts, for example, within the frame of international multicentre collaborations. For these reasons, it is not surprising that drug development in SLE has not been as expeditious as in more common and less heterogeneous rheumatic diseases, such as rheumatoid arthritis.

 

Towards optimisation of the management of SLE, it is important that research focuses on: (i) a better understanding of autoimmunity underlying clinical phenotypes in order to identify adequate drug targets; (ii) in depth investigation of the effects of currently available therapies in order to improve their use; and (iii) better trial designs, including the choice of coherent outcome measures. In order to achieve these goals, it is important to remain receptive to new classification concepts. For example, studying new drugs in patients showing specific clinical patterns rather than in SLE at large might conceivably result in more homogeneous study populations. Another example might be stratification of SLE patients into subsets based on distinct immunological profiles such as interferon signature genes or autoantibody expression patterns.

 

Last, but not least, the patients’ perspective should be taken into consideration when studying drug effects. Self-perceptions of HRQoL, fatigue, pain and functional disability should be an integral part of the clinical assessment. A new drug cannot be considered effective if it does not significantly improve the patients’ HRQoL. 

 

1 Tsokos GC. Systemic lupus erythematosus. N Engl J Med 2011;365:2110–21.

2 Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:929–39.

3 Ronnblom LE et al. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 1991;115:178–83.

4 King JK, Hahn BH. Systemic lupus erythematosus: modern strategies for management: a moving target. Best Pract Res Clin Rheumatol 2007;21:971–87.

5 Yildirim-Toruner C, Diamond B. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol 2011;127:303–12; quiz 13–14.

6 Boyce EG, Fusco BE. Belimumab: review of use in systemic lupus erythematosus. Clin Ther 2012;34:1006–22.

7 Parodis I, Axelsson M, Gunnarsson I. Belimumab for systemic lupus erythematosus: a practice-based view. Lupus 2013;22:372–80.

8 Ruiz-Irastorza G, Khamashta MA. Hydroxychloroquine: the cornerstone of lupus therapy. Lupus 2008;17:271–3.

9 Ruiz-Irastorza G et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8.

10 Levy RA et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 2001;10:401–4.

11 Pons-Estel GJ et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61:830–9.

12 Hench PS et al. The effects of the adrenal cortical hormone 17-hydroxy-11-dehydrocorticosterone (Compound E) on the acute phase of rheumatic fever; preliminary report. Proc Staff Meet Mayo Clin 1949;24:277–97.

13 Apostolopoulos D, Morand EF. It hasn’t gone away: the problem of glucocorticoid use in lupus remains. Rheumatology (Oxford) 2017;56(suppl_1):i114-i122.

14 Bertsias G et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195–205.

15 Barile-Fabris L et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis 2005;64:620–5.

16 Contreras G et al. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus 2005;14 Suppl 1:s33–8.

17 Houssiau FA 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;46:2121–31.

18 Boumpas DT et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741–5.

19 Austin HA 3rd et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986;314:614–19.

20 Gourley MF et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996;125:549–57.

21 Houssiau FA. Therapy of lupus nephritis: lessons learned from clinical research and daily care of patients. Arthritis Res Ther 2012;14:202.

22 Gunnarsson I et al. Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum 2007;56:1263–72.

23 Mok CC. Pro: The use of calcineurin inhibitors in the treatment of lupus nephritis. Nephrol Dial Transplant 2016;31:1561–6.

24 Fei Y et al. Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Clin Exp Rheumatol 2013;31:62–8.

25 Li X et al. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012;27:1467–72.

26 Hannah J, Casian A, D’Cruz D. Tacrolimus use in lupus nephritis: A systematic review and meta-analysis. Autoimmun Rev 2016;15:93–101.

27 Alexander T et al. The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 2015;74:1474–8.

28 Monneaux F et al. T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice. Eur J Immunol 2003;33:287–96.

29 Monneaux F et al. Intramolecular T cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151. Arthritis Rheum 2004;50:3232–8.

30 Monneaux F et al. Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. J Immunol 2005;175:5839–47.

31 Monneaux F et al. Importance of spliceosomal RNP1 motif for intermolecular T-B cell spreading and tolerance restoration in lupus. Arthritis Res Ther 2007;9:R111.

32 Page N et al. The spliceosomal phosphopeptide P140 controls the lupus disease by interacting with the HSC70 protein and via a mechanism mediated by gammadelta T cells. PLoS One 2009;4:e5273.

33 Page N et al. HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus. Ann Rheum Dis 2011;70:837–43.

34 Zimmer R et al. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis 2013;72:1830–5.

35 Navarra SV et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721–31.

36 Furie R 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;63:3918–30.

37 Baker KP et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum 2003;48:3253–65.

38 Terrier B 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;62:2458–66.

39 Diaz-Lagares C et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 2012;11:357–64.

40 Boletis JN et al. Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study. Nephrol Dial Transplant 2009;24:2157–60.

41 Jonsdottir T et al. Clinical improvements in proliferative vs membranous lupus nephritis following B-cell depletion: pooled data from two cohorts. Rheumatology (Oxford) 2010;49:1502–4.

42 Jonsdottir T et al. Rituximab-treated membranous lupus nephritis: clinical outcome and effects on electron dense deposits. Ann Rheum Dis 2011;70:1172–3.

43 Li EK et al. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rheumatology (Oxford) 2009;48:892–8.

44 Pepper R et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant 2009;24:3717–23.

45 Sfikakis PP et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum 2005;52:501–13.

46 Vigna-Perez M et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006;8:R83.

47 Leandro MJ et al. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002;46:2673–7.

48 Looney RJ et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004;50:2580–9.

49 Leandro MJ et al. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005;44:1542–5.

50 Ng KP et al. Repeated B cell depletion in treatment of refractory systemic lupus erythematosus. Ann Rheum Dis 2006;65:942–5.

51 Jonsdottir T et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis 2008;67:330–4.

52 Jonsdottir T et al. Long-term follow-up in lupus nephritis patients treated with rituximab – clinical and histopathological response. Rheumatology (Oxford) 2013;52:847–55.

53 van Vollenhoven RF et al. Biopsy-verified response of severe lupus nephritis to treatment with rituximab (anti-CD20 monoclonal antibody) plus cyclophosphamide after biopsy-documented failure to respond to cyclophosphamide alone. Scand J Rheumatol 2004;33:423–7.

54 Rovin BH et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64:1215–26.

55 Merrill JT 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;62:222–33.

56 Bertsias GK 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;71:1771–82.

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

58 Ramos-Casals M et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010;28:468–76.

59 Witt M et al. Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) – results from a nationwide cohort in Germany (GRAID). Lupus 2013;22:1142–9.

60 Ryden-Aulin M et al. Off-label use of rituximab for systemic lupus erythematosus in Europe. Lupus Sci Med 2016;3:e000163.

61 van Vollenhoven RF et al. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum 2011;63:1782–92.

62 Ginzler EM et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther 2012;14:R33.

63 Furie RA et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis 2015;74:1667–75.

64 Isenberg DA 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 2016;75:323–31.

65 Merrill JT 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 2016;75:332–40.

66 Gatto M et al. Success and failure of biological treatment in systemic lupus erythematosus: A critical analysis. J Autoimmun 2016;74:94-105.

67 Houssiau FA, Doria A. Targeting BAFF/BLyS in lupus: is the glass half-full or half-empty? Ann Rheum Dis 2016;75:321–2.

68 Wallace DJ 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;52:1313–22.

69 Wallace DJ 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;73:183–90.

70 Clowse MEB et al. Efficacy and safety of epratuzumab in patients with moderate-to-severe systemic lupus erythematosus: Results from two phase 3 randomized, placebo-controlled trials [abstract]. Arthritis Rheumatol 2015;67.

71 Liang B et al. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 2006;119:296–305.

72 Kiberd BA. Interleukin-6 receptor blockage ameliorates murine lupus nephritis. J Am Soc Nephrol 1993;4:58–61.

73 Rovin BH et al. A Multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of treatment with sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis Rheumatol 2016;68:2174–83.

74 Illei GG 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;62:542–52.

75 Ronnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 2008;17:394–9.

76 Khamashta M et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:1909–16.

77 Kalunian KC et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-alpha) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis 2016;75:196–202.

78 Furie R et al. Anifrolumab, an anti-interferon alpha receptor monoclonal antibody, in moderate to severe systemic lupus erythematosus (SLE) [abstract]. Arthritis Rheumatol 2015;67.

79 Merrill JT 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;62:3077-87.

80 van Vollenhoven RF, Parodis I, Levitsky A. Biologics in SLE: towards new approaches. Best Pract Res Clin Rheumatol 2013;27:341–9.

81 Furie R et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 2014;66:379–89.

82 Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum 2012;64:3660–5.