Biologics in the Treatment of Systemic Lupus Erythematosus

Aisha Lateef; Michelle Petria


Curr Opin Rheumatol. 2010;22(5):504-509. 

In This Article

B-cell Targets

B cells have been targeted in several ways in SLE. B-cell depletion can be achieved by targeting the CD20 [rituximab (RTX)]. B-cell modulation without depletion targets CD22 (ezpratuzumab). Other approaches targeting B cells include blocking the B-cell growth factors (BLyS) or the cross-talk between B and T cells by co-stimulation blockade.


A large body of literature, mostly in open studies, has documented the efficacy of RTX in severe refractory SLE. Two randomized double-blind, placebo-controlled trials[10,11••] were designed to objectively assess the efficacy and safety of RTX in a rigorous scientific manner. Quite unexpectedly, both trials were negative.

Efficacy and Safety of Rituximab in Patients with Severe SLE (EXPLORER) was a randomized, double-blind, placebo-controlled trial of RTX for nonrenal SLE.[11••] A total of 257 patients with moderate-to-severe active disease (defined as at least one BILAG A score or two BILAG B scores) were randomized to RTX versus placebo. They received intravenous placebo or RTX (1000 mg on day 1, 15, 168, 182) infusions on background of a single stable immunosuppressant (azathioprine 100–250 mg/day, mycophenolate mofetil 1–4 gm/day or methotrexate 7.5–27.5 mg/week). In addition, all patients received a 10-week course of increased glucocorticoids (0.5–1.0 mg/kg). Major clinical response (MCR) was defined as achievement of a BILAG C score in all organ systems without new flares. Partial clinical response (PCR) was achievement of BILAG B or C scores with no major flares. No significant difference was noted between the groups: MCR was 15.9 versus 12.4% and PCR was 12.5 versus 17.2% for placebo and RTX groups, respectively. A prespecified sub-group analysis in African American and Hispanic patients showed more benefit of RTX, 33.8 versus 15.7% over other ethnic groups. RTX was noted to be biologically active, with significant improvement in immunological parameters, including anti-double-stranded DNA (anti-dsDNA) antibody and complement levels in the RTX group compared with placebo.[11••]

Although this was a robust trial, there are potential reasons why a beneficial effect of RTX might have been missed. The majority of patients had mucocutaneous and musculoskeletal involvement, which represent relatively milder forms of SLE. Patients with severe refractory disease, the subgroup in which RTX has shown efficacy in open-label studies, may have been under-represented. Both the placebo and the RTX arms received high doses of corticosteroids, and therapeutic doses of background immunosuppressants. High-dose corticosteroids are known to improve disease activity in SLE, and this may have prevented the assessment of RTX benefit. The follow-up duration was 52 weeks, perhaps insufficient to assess long-term outcome in a chronic disease such as SLE. Prior open-label studies have shown maximal clinical benefit to be evident even after 18 months.[16]

Immunologists have suggested additional reasons why the trial may have missed its primary outcome. Some patients, after RTX, reconstitute with naive B cells, which are more receptive to tolerance induction.[17] One would not want to re-deplete these patients by RTX re-treatment. Other patients, especially those who do not deplete B cells completely, reconstitute with memory B cells.[17,18] These patients might benefit from RTX re-treatment. In EXPLORER, there was no B-lymphocyte typing and all patients were re-treated at 6 months.

The second large trial, LUNAR (The Efficacy and Safety of Rituximab in class III or IV lupus nephritis), compared RTX therapy versus placebo, when added to background of steroids and mycophenolate mofetil.[10] A total of 144 patients were randomized to receive placebo or RTX in a protocol similar to EXPLORER. The results, available as an abstract, did not show any significant difference in the two treatment arms in any primary or secondary outcomes. Again, African American and Hispanic subgroups showed a better response, but failed to meet statistical significance.[10]

In contrast to these negative studies, multiple open-label studies continue to report the efficacy of RTX in patients with severe refractory SLE and catastrophic antiphospholipid syndrome.[2–4,5•,6,7•,8•,9] The majority of patients receiving RTX in these studies have failed multiple prior immunosuppressants and have multisystem severe life or organ-threatening disease. A recent review[19•] evaluated the use of RTX in 188 SLE patients from 35 studies, reporting efficacy rates approaching 90%. Similarly high response rates were reported in a meeting by multiple experts using RTX in SLE in ongoing studies at tertiary referral centers.[16]

Despite the weakness of the open label design of these studies, the very large response is difficult to be ignored. Although RTX cannot be considered first-line therapy for mild-to-moderate SLE, the benefit in severe refractory disease may justify its use in such cases. The differential response seen in different ethnic groups should be explored further.

Safety Issues with Rituximab

Concerns about the safety of B-cell depletion in SLE were raised after reports of progressive multifocal leukoencephalopathy (PML) in SLE patients treated with RTX. SLE patients have an inherently higher risk of PML, even with minimal or no immunosuppression.[20] A few cases of PML in RTX-treated patients (rheumatoid arthritis and SLE) have been reported by the manufacturer. The United States Food and Drug administration (FDA) has issued an alert about possible RTX and PML link after reports of PML in RTX -treated patients with SLE and rheumatoid arthritis.[21] More data are required to evaluate if RTX increases this inherent risk unacceptably in SLE. EXPLORER and LUNAR did not report any significant increase in serious adverse effects in the RTX-treated group. However, higher rates of neutropenia and herpes infections were reported at 72 weeks' follow-up of patients in EXPLORER.[22]


The anti-CD-22 monoclonal antibody, epratuzumab, modulates B-cell function without B-cell depletion. Epratuzumab was evaluated in two randomized controlled trials in patients with moderate-to-severe SLE flares. Unfortunately, both trials were terminated prematurely due to interruptions in biologic supply. Ninety patients were enrolled in the study before termination. Epratuzumab was effective and led to improvements in BILAG scores and reduction in corticosteroid doses with a good safety profile.[23,24] Two studies are currently evaluating the efficacy of epratuzumab in a subset of serologically active SLE.[25,26]


The B-lymphocyte stimulator (BLyS) is important for the survival of B cells. Animal and human data have shown overexpression of BLyS in SLE.[27] In a longitudinal study, higher BLyS levels correlated with SLE disease activity.[28••] Belimumab is a fully human monoclonal antibody that binds to BLyS and inhibits its biological activity. Efficacy, tolerability and safety of three different doses of belimumab in SLE were evaluated in a multicenter phase 2 study.[29•] A total of 449 patients were randomized to receive 1, 4 or 10 mg/kg of belimumab or placebo intravenously (at day 0, 2 and 4 weeks and then 4 weekly for 52 weeks). All received standard of care (corticosteroids and immunosuppressants) in addition to belimumab. The co-primary endpoints included percentage change in the activity index [Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)] and the time to a lupus flare [defined by SELENA–SLEDAI flare index (SFI)]. There was no significant difference in either outcome in the combined belimumab group versus placebo. In the subgroup of serologically active patients [positive antinuclear (ANA) and/or anti-dsDNA antibody], belimumab did lead to a significantly better response over placebo. Belimumab treatment led to a significant reduction in B-cell counts, immunoglobulin levels, and anti-dsDNA antibody levels. Complement levels rose in patients with baseline low levels of complement.[29•] The limitations of this study were the unlimited changes in corticosteroid doses and immunosuppressants, confounding the disease activity assessments. Inclusion of seronegative (negative ANA and/or anti-dsDNA antibody) patients (28%) was another potential problem. This trial was later continued as an open-label extension study.[30] Four-year safety and efficacy data for 237 patients have recently been reported. Serologically active patients showed sustained improvement in all flares and severe flares over time. There were reductions in multiple pathogenic autoantibodies, including anti-dsDNA and anticardiolipin.[30]

Belimumab was further evaluated in two large randomized, double-blind, placebo-controlled, multicenter phase 3 trials, BLISS-52 and BLISS-76,[31,32] including 865 and 826 seropositive (ANA and/or anti-dsDNA) patients, respectively. In each of these trials, patients were randomized to receive 10 mg/kg belimumab, 1 mg/kg belimumab, or placebo. Patients were dosed intravenously on days 0, 14 and 28, then every 28 days thereafter for the duration of the study. All patients received standard-of-care therapy in addition to the study medication. The primary efficacy endpoint was the SLE responder index at week 52 (defined as at least four-point reduction in SELENA-SLEDAI, no new BILAG A score and no worsening of disease activity by physician global assessment).[33] Belimumab achieved significantly better results than placebo in both studies. In BLISS-52, response rates were 51.7% for belimumab 1 mg/kg and 57.6% for 10 mg/kg belimumab, compared with 43.6% for placebo.[32] In BLISS-76, response rates were 43.2% for 10 mg/kg belimumab, 40.6% for 1 mg/kg belimumab, and 33.8% for placebo.[31] In addition, belimumab significantly delayed time to first SLE disease flare versus placebo and lead to significant reduction in steroid doses in BLISS-52.[32] Belimumab was well tolerated, with rates of overall adverse events, serious adverse events, infections and fatalities comparable between belimumab and placebo groups.[31,32] These significantly positive results in both phase 3 studies have raised the hopes that belimumab may be the long-awaited new effective therapy for SLE.


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