BLM is a human monoclonal antibody that inhibits soluble B lymphocyte stimulator, a key cytokine to the survival of B cells, which is overexpressed in33–39 SLE.

In the initial phase II placebo-controlled trial, BLM did not achieve the objectives of efficiency based on the SELENA-SLEDAI activity index at weeks 24 and 52.40 However, post hoc analysis showed that BLM significantly reduced disease activity in patients with anti-nuclear (ANA) and anti-DNA positive antibodies. This is why the BLM registration trials (BLISS-5241 and BLISS-7642 included only patients with positive ANA and/or anti-dsDNA, with SELENA-SLEDAI of ≥6. Patients were randomized to receive intravenous infusions 1mg/kg of BLM, 10mg/kg of BLM or placebo on days 0, 14, and 28 and then every 28 days. The primary outcome measure was a response on the SLE Reply Index (SRI) at week 52, defined as a ≥4-point reduction in the SELENA-SLEDAI, no BILAG A, no more than one BILAG B or lack of worsening in GPhA.

In BLISS-5241 there were significantly higher percentages of patients with a response and an SRI reduction ≥4 points in the SELENA-SLEDAI, and lower rates of new BILAG A or B and GPhA worsening in the BLM vs the placebo group. In BLISS-7642 a higher percentage of patients in the BLM 10mg/kg group achieved an SRI response at week 52 compared to placebo (P=.017). In two randomized clinical trials (RCTs), the rate of adverse events was similar across treatment groups.

There is no evidence in connection with the use of BLM in manifestations of SLE such as lupus nephritis or severe neurological manifestations, as patients with these two types of involvement were specifically excluded from the trials. In a post hoc analysis of the fundamental phase III trials, a beneficial effect of BLM on renal outcome measures in patients with non-severe renal impairment has been suggested.43 Likewise, another recently published post hoc analysis has shown a beneficial effect on cutaneous and musculoskeletal manifestations.44,45

The panel recommends the use of BLM in adult patients with active SLE with positive autoantibodies and high disease activity despite standard therapy (LE 1; DR, DA 93%). Today, patients with refractory non-major clinical manifestations (such as arthritis or skin involvement) and laboratory activity seem to be the most appropriate clinical setting for use of this agent.

Currently, we cannot recommend the use of BLM in patients with SLE and severe involvement of the central nervous system (CNS) and/or severe lupus nephritis (LE 1; DR, DA 93%).

Although the safety profile shown by BLM in clinical trials was good, there is still little experience in long term use. Follow-up experience of the first patients entered into clinical trials with this drug and who continued using it in later extension stages for 4 years that was recently published (total experience of 1165 patient-years), observed that the incidence of adverse effects, including infusion reactions, infections, malignancies, laboratory abnormalities, or the number of withdrawals from treatment due to unwanted effects, were stable or declining.46

In a patient with SLE who is to initiate treatment with BLM, it is important to consider the possible co-existence of infections, cancer, heart failure, cytopenias or other significant comorbidity that should be monitored, or a contraindication to starting treatment.

An active systemic or localized infection is a contraindication for the start of BLM (LE 2b, DR B, DA 100%). In case of chronic, recurrent or high risk of infection, risk-benefit of its employment should be assessed strictly for close monitoring. One must also pay special attention to the possible development of infections during treatment. If this occurs, diagnosis and treatment of cases are essential and the temporary suppression of BLM. Once infection is resolved, you can restart BT.

Risk of BLM use in patients with active or latent tuberculosis (BT) is unknown. The panel advises to follow the general recommendations for the use of biological therapies in rheumatic diseases, which can be found on the BE Consensus document on managing the risk of treatment with biological therapies in patients with rheumatic diseases.32

Prior to the start of the BLM, one must take into account the history of malignancies and lymphoproliferative disorders (LE 5, DR D, DA 100%). When a history of this exists, special caution is needed for its use, although no evidence of increased risk of solid tumors in patients treated with BLM. If malignancy is diagnosed during treatment with BLM, it should be suspended.

Before starting treatment with BLM, the existence of cytopenias must be evaluated. If attributed to SLE, treatment could be started cautiously. Otherwise, one should not start treatment until resolution (LE 5, DR D, DA 100%). If the patient develops severe cytopenia during treatment with BLM, we recommend stopping and looking for other potential causes. After resolution, treatment may be restarted.

HBV and HCV serology is advised. Administration of pneumococcal and influenza vaccine prior to starting treatment with BLM is recommended (LE 3b, DR C, DA 100%). We discourage the use of vaccines with live or attenuated germs within 30 days or simultaneously with the use of BLM.

BLM is not recommended in patients >65 years, unless the expected benefits outweigh the risks. It is also not recommended for use in patients with CNS manifestations, severe active lupus nephritis, human immunodeficiency virus infection, a history of or active HBV or HCV infection, hypogammaglobulinemia (IgG <400mg/dl) or IgA deficiency (IgA <10mg/dl), a history of major organ transplant or hematopoietic stem cell/bone marrow transplantation or kidney transplant, as it has not been used in those situations (LE 5, DR D, DA 93%).

BLM is not recommended for use with other treatments acting on B cells or cyclophosphamide (CFM) (LE 5, DR D, DA 93%).

BLM does not require dose adjustment in patients with mild, moderate or severe renal failure. However, due to the absence of data, caution is recommended in patients with severe renal impairment (LE 5, DR D, DA 93%).

Pregnancy should be avoided during treatment with BLM and in the 4 months after completion. BLM should not be used during pregnancy unless clearly necessary (LE 5, DR D, DA 100%). Regarding breastfeeding, you should consider the benefit of it to the child and the benefit of treatment with BLM for mother and decide.

In patients who are to undergo a surgery in the absence of sufficient experience to date, the panel recommends BLM suspended in the 2 weeks before surgery and resumed 2–4 weeks after surgery, given the increased risk of infections, cytopenias, and coagulation disorders in this period (LE 5, DR D, DA 100%).

During follow-up, conduct a clinical and laboratory evaluation of the patient, with a periodicity of monthly visits at baseline and then 1–3 months, depending on the patient's progress (LE 5, DR D, DA 100%).

Rituximab (RTX) is a soluble chimeric monoclonal antibody directed against the CD20 membrane receptor, present in most cellular phases of B cell ontogeny (from pre-B cell to memory B cell), but not in the plasma cell. Infusing this antibody produced, by various mechanisms (cytotoxicity mediated and non-mediated by antibodies and antibody-mediated apoptosis) a depletion of the population of cells over a period of 6 months or more.

Currently, RTX has no approved indication for SLE. However, there are numerous open studies that support the use of RTX in various situations, including some serious such as nephritis, cytopenias or nervous system involvement. However, the EXPLORER study was unable to prove superiority of RTX vs placebo associated with conventional treatment in patients with active lupus in its primary stage (whose objective was to achieve and maintain a clinical response at week 52 using an 8 organ BILAG).47 This double-blind Phase II/III RCT evaluated the efficacy and safety of RTX (2 doses of 1g separated by 14 days) or placebo added to standard therapy (varying doses of glucocorticoids, azathioprine [AZA], mycophenolate mofetil [MMF] or methotrexate [MTX]) in 257 patients with lupus without renal involvement or with moderate to severe activity. They have suggested various design issues that could explain this unfavorable outcome such as it being underpowered to demonstrate differences between 2 groups of patients with active medication, the use of varying doses of glucocorticoids and immunosuppressant, limited follow up time (one year may not allow a deferred evaluation of therapeutic effects) or insensitivity to the improvement criteria. Another RCT conducted in patients with lupus nephritis, the LUNAR study,48 which will be discussed below, also identified an additional benefit associated to the use of RTX. However, this study also suffered from methodological problems similar to the EXPLORER.49

The specific dose of RTX for SLE has not been established. In clinical trials it has generally been used in the same way as in rheumatoid arthritis, infusing two 1g doses47,48,50–52 14 days apart. However, numerous studies have used it as in lymphoma treatment, 4 weekly infusions of 375mg/m.2,53,54 It has even been suggested that a pattern shorter than 4 weekly infusions of 100mg may be effective.55

The convenience of managing RTX as monotherapy or in combination with other immunosuppressants has not been established. In most of the open studies 2 intravenous doses of 500–750CFMmg on days 3 and 17 have been associated to the standard dose of 375mg/m2 of RTX. However, this combination has not demonstrated any advantage in the induction treatment of lupus nephritis.56 in the LUNAR48 study, all patients received MMF concomitantly, which does not allow the drawing of conclusions on the desirability of the combination of drugs. Recently, the appearance of progressive multifocal leukoencephalopathy has been seen in SLE patients treated with RTX with previous or concomitant use of alkylating agents.57

In the AIR58 registry, the combination with any immunosuppressant, including CFM, obtained significant drops in SELENA-SLEDAI scores 6±3 months after infusion and longer times to recurrence.59 In the LESIMAB cohort, any concomitant immunosuppressant other than the CFM were 3.5 times more likely to achieve a clinical response after a mean follow-up of 20±15.2 months. In the series by Vital et al.,60 patients who were receiving concomitant immunosuppressive outperformed monotherapy patients, with no differences between the different drugs.

The panel recommends keeping previous immunosuppressive therapy in patients with SLE in which treatment was started if there was an inadequate response to them (LE 4, DR C, DA 86%). However, the panel calls attention to the potential risks of combined use with certain immunosuppressants, such as CFM, in which case the risk should be balanced against the seriousness of the event in question (LE 5; DR D, DA 93%).

Patients in particularly serious situations have also been used in combination with bolus glucocorticoids and RTX or without CFM bolus. Glucocorticoid doses also varied, depending on the patient.

In the LUNAR and EXPLORER RCTs, the RTX dose was repeated at 6 months after initial treatment and the observational study by Turner-Stokes et al.61 suggests that the constant repetition of doses of RTX is more convenient than on-demand treatment. However, and even though it seems that the majority of SLE patients require repeated cycles, it has been more widely used on demand in patients with an initial response. In the absence of lupus activity, the panel does not recommend the routine administration of new cycles of RTX, except in patients with particularly severe flares of disease, in which a new flare could bring dire consequences (LE 5, DR D, DA 79%).

RTX should be reserved for patients with a moderately or severely inadequate response, or resistant to standard treatment with corticosteroids, immunosuppressants (AZA, MTX, MMF, CFM or calcineurin inhibitors) and BLM (depending on the event in question) (LE 2b, DR B, DA 93%). The need for a relatively high dose of glucocorticoids to maintain control of the disease may also be an indication (Table 5).

In relation to risk management, retreatment with RTX is safe for at least 6–12 months.70 In the absence of specific pharmacovigilance data, we recommend following the risk management directions issued for RTX use in other chronic inflammatory joint diseases (LE 5, DR D, DA 93%).

Levels of serum TNF-α are greatly increased in SLE patients and correlate with disease activity.71–73 That is why, a priori, their blockade could be effective in treating these patients.

In relation to the available evidence on efficacy and safety with these agents in SLE, it should be noted that only 2 RCTs with infliximab (IFX) and etanercept (ETN) double blind placebo prematurely closed to,74,75 for what is currently available data are based on small uncontrolled open studies or case series.

In a publication showing data76 of 13 patients refractory to standard therapy, 6 from a previous open study77 and 7 from various centers, it was found that a cycle of four IFX infusions improved immunosuppression with lupus nephritis (III, IV, V) in terms of improvement of >50% in proteinuria, and stabilization of serum creatinine in 7 of 9 patients, 4 of which remained stable over time (up to 5 years) and 3 worsened despite new IFX cycles. The 5 patients with arthritis went into remission, but chronic treatment maintained its effect only in 2 patients. In another open study with 11 patients78 it was found that IFX treatment for 6 months was superior to standard therapy in the improvement in SLEDAI but no difference was seen in steroid dose changes, SF-36, SLICC/ACR/DI, proteinuria, complement or autoantibody levels. A third open IFX study showed very similar results to the prior ones.79 On the other hand, there are cases or case series on the use of IFX in patients with pulmonary involvement or hemphagocytic lymphohistiocytosis.76,80–82

There are some case reports of patients with SLE and ETN.83–85 Similarly, there is insufficient evidence regarding the use of adalimumab, certolizumab and golimumab, or on the use of anti-TNF-α for other relevant clinical manifestations of SLE.

In patients with corticosteroid refractory lupus nephritis and immunosuppressants, including CFM, AZA and MMF, and RTX, the possibility of a short course of anti-TNF and off-label therapy can be assessed (LE 4, DR C, DA 73%).

In patients with SLE and arthritis, using anti-TNF agents could be justified only in cases of failure to standard immunosuppressive therapy, as well as other biological therapies (or inability to use them), such as BLM, RTX and probably ABT. In any case, its use should be only after a careful analysis of the risk/benefit (LE 5, DR D, DA 73%).

Regarding risk management of the use of anti-TNF, given the small number of patients and the exposure time we cannot draw conclusive data. There are reports of serious infections and lymphoma. It has also been observed that short term treatment with IFX leads to transient increases of autoantibodies in the long term and may increase the levels of anti-dsDNA.76 In the same way, there is at least one case described of a patient who developed deep vein thrombosis that could be related to the medication, suggesting that it may be more common in type V lupus nephritis.86

In the absence of specific pharmacovigilance data, we recommend following the directions issued on risk management on the use of anti-TNF in other chronic inflammatory joint diseases (LE 5, DR D, DA 100%).

Caution is advised in patients with nephrotic syndrome and/or massive proteinuria (more common in type V lupus nephritis), in whom anti-TNF used should be balanced against the potential risk of developing deep vein thrombosis (LE 5, DR D, DA 86%).

ABT is a fusion protein consisting of the extracellular domain of human CTLA-4 linked to an Fc fragment of human IgG1. ABT selectively inhibits lymphocyte costimulation blocking the binding of CD80/CD86 to CD28 without causing T cell depletion.87

The efficacy and safety of ABT in patients with SLE have been studied in RCTs in two distinct situations, on the one hand, in patients with active extrarenal manifestations88 and, more recently, in patients with lupus nephritis.89

A double-blind, placebo controlled trial88 evaluated the efficacy and safety of ABT in SLE patients without renal involvement. It enrolled 180 patients with active disease (polyarthritis, serositis and discoid lupus), who were randomized to receive ABT 10mg/kg or placebo for one year. All patients received prednisone (30mg/day for a month and then tapering). No significant differences in the proportion of patients with a new flare of SLE (BILAG A or B) after starting prednisone tapering or any of the secondary BILAG dependent objectives were seen.

A post hoc analysis showed a greater efficacy of ABT in polyarthritis (62.5% vs 36.5%), assessment of the flare by the physician (82.3% vs 63.6%) and the proportion of patients without recurrence during months 10–12 when treated with doses of 7.5mg/day of prednisone (42.4 vs 28.1) or lower. ABT showed some efficacy in patient-dependent variables (SF-36, fatigue or sleep disorders). The frequency of serious adverse events was higher in the ABT group (19.8 vs 6.8).

Another double-blind, placebo-controlled study89 evaluated the efficacy and safety of ABT in 298 patients with active class III or IV lupus nephritis. Patients received ABT 10mg/kg/month for 12 months, or 30mg/kg/month for 3 months followed by 10mg/kg/m or placebo for 9 months to one year. All patients received MMF 1.5–3g/d, prednisone (up to 60mg/day for a month, and then in descending pattern). No significant differences between groups in terms of time to complete renal response or in the secondary objectives were seen. In a subanalysis of patients with nephrotic syndrome (n=122), there was a trend toward greater ABT efficacy in reducing proteinuria after the sixth month, maintained until the end of the study.

These negative results contrast with ABT in RCT data from animal models, and clinical experience outside of clinical trials. Study design aspects, such as its short duration, non-validated outcomes, heterogeneous populations or concomitant use of highly effective therapies appeared to contribute clearly to the negative results of these RCTs.90,91 In the case of ABT, the possible efficacy in subgroups of patients with polyarthritis or nephrotic syndrome suggests at least some usefulness in some patients with SLE.92

The panel does not recommend the use of ABT for the treatment of SLE, or its renal and extrarenal manifestations (LE 1; DR, DA 93%).

However, in patients with polyarthritis refractory to other therapies, and in which no other therapeutic option was possible, ABT may be useful (LE 4; DR D; DA 86%).

In the absence of specific pharmacovigilance data, we recommend following the directions issued on ABT risk management used for other chronic inflammatory joint diseases (LE 5, DR D, DA 100%).

Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the receptor for IL-6. It suppresses both soluble and membrane-bound IL-6 receptor-mediated signaling soluble IL-6.93 In SLE there is increased serum IL-671,73,86,94–96 which is clinically related to activity and the concentration of anti-dsDNA antibodies.

There are no double-blind RCTs demonstrating the efficacy of TCZ in the treatment of SLE. Shirota et al.97 reported in 2005 the results of a study in which TCZ infusions were administered biweekly at doses of 2mg/kg (n=4), 4mg/kg (n=6) or 8mg/kg (n=3) for 12 weeks to patients with SLE, with subsequent follow-up visits at 8 weeks. It was observed that treatment with TCZ decreases lymphocyte activation, the homeostasis of T and B cells, blocking their differentiation and/or trafficking in SLE patients, normalizing abnormal T cell and B subsets.

In an open dose escalation98 study which evaluated the safety and efficacy of TCZ in 16 patients with moderately active SLE, 7 infusions were administered biweekly (2mg/kg in 4 patients, 4mg/kg in 6 patients and 8mg/kg in another 6) for 12 weeks, with a follow-up of 8 weeks. There was dose-related neutropenia, recovering after discontinuation of treatment. Unrelated infections were observed in 11 cases. There was an improvement in the SELENA-SLEDAI score in 8 of 15 patients and improvement in 7 patients that had arthritis at baseline and which resolved completely in 4. However, no improvement of proteinuria was seen in the 5 patients with nephropathy. The levels of anti-dsDNA IgG and decreased in the 4 and 8mg/kg groups, suggesting a specific of TCZ on autoantibody producing cells. Although TCZ has been associated to increased ALT/AST and cholesterol related to RA,99,100 the latter study98 showed no significant changes in the serum concentrations in patients with SLE. In all cases there was a significant decrease in erythrocyte sedimentation rates and C reactive protein levels.

The panel proposes to consider the use of TCZ in selected patients with SLE refractory to conventional treatments (hydroxychloroquine, corticosteroids, AZA, MTX, cyclosporine, and MMF CFM) who do not respond or are intolerant to BLM and RTX (LE 4, DR C, DA 86%).

Regarding risk management of the use of TCZ, given the low patient volume and exposure time, no conclusive data can be extracted. Neutropenia has been described and it has been observed that short term treatment with transient increases transaminases, triglycerides and cholesterol occurs in patients with RA treated with TCZ, although this effect was not observed in SLE.

In the absence of specific pharmacovigilance data, we recommend following the TCZ use directions issued on risk management in other chronic inflammatory joint diseases (LE 5, DR D, DA 100%).

The CD22 antigen is a 135kDa glycoprotein that is expressed in and restricted to B lymphocytes and participates regulating its activation and interaction with T cells.101 It is expressed in the cytoplasm of pro-B and pre-B cells, and on the surface of mature B cells. Epratuzumab is a recombinant anti-CD22monoclonal antibody, with a 90%–95% human origin. It primarily has an immunomodulatory effect on B cells, unlike RTX, which is primarily a cytotoxic agent.

Atacicept is a chimeric fusion protein of the extracellular domain of Transmembrane Activator and Calcium receptor modulator and cyclophilin ligand Interactor (TACI) domain linked to human IgG1, which blocks the stimulation of B cells dependent on Blys and APRIL. Studies in mouse models and in humans have shown a marked reduction in the levels of immunoglobulins (including autoantibodies) after treatment, due to its effect on plasma cells.

Costimulation signals promote T-cell differentiation, proliferation and activation of B cells Of all known costimulatory pathways, in SLE those studied have only been those specifically composed by CD40-CD40 ligand (CD40L or CD154) and B7-CD28. CD40L-neutralizing antibody may interfere with reactions occurring in the germinal centers and also reduce activation of B lymphocytes in the marginal zone.102 Some studies in SLE patients have been prematurely ended due to thromboembolic complications.

There have been other three trials with IDEC-131, a monoclonal antibody against CD154, which have included a total 110 patients103–105 and have demonstrated good safety and tolerability in patients with SLE. Regarding efficiency, no significant differences over placebo have been achieved.105

The inducible costimulator (ICOS) is a T cell-specific molecule, structurally and functionally related to CD28. It is induced on the surface of T cells after these are activated. It transmits costimulation signals in T cell. ICOS and its ligand are involved in the interaction between T and B cells, and differentiation of the latter. Although it looks like a promising therapeutic target in murine lupus models, there is no experience in humans.106 Finally, and related to costimulatory molecules, there is now a phase I trial with anti-B7RP1 (AMG557) underway in patients with SLE.

Although the role of IL-10 in the pathogenesis of SLE is not completely defined, it seems to be involved in B cell hyperactivation and antibody production. A murine monoclonal antibody has been developed which neutralizes human IL-10 (B-N10), with a small open study in 6 patients showing improvement in clinical activity and reduced use of prednisone. However, this agent has not had any further clinical development.107

IFN-a is a pleiotropic cytokine that is essential in the pathogenesis of SLE.108 Its levels are increased in serum of patients with SLE, the gene expression profile of the peripheral blood mononuclear cells is dependent on IFN-α and, finally, the serum of SLE patients is able to induce the maturation of dendritic cells, which is also dependent effect of IFN-α. Almost two-thirds of patients with SLE show common features related to IFN-α. In mice, its involvement has been demonstrated in B cell dependent lymphopenia, differentiation of germinal centers and generation of plasma cells. Hence it is considered as a very good therapeutic target. To date, two monoclonal antibodies against IFN-α have been tested, sifalimumab and rontalizumab. However, results of a phase II of the latter agent109 recently reported seem to show no differences from placebo.

Recently, new, humanized anti-CD20 monoclonal antibodies have been designed, such as ofatumumab (HuMax CD20), IMMU-106 (hA20), GA-101, with high cytotoxic potential on B cells. Experience is limited to preclinical studies and they have not been tested yet in patients with SLE.

Finally, eculizumab is an antibody that specifically inhibits terminal activation of complement.110