Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arthritis Rheum. Author manuscript; available in PMC Jul 1, 2013.
Published in final edited form as:
PMCID: PMC3350827

Belimumab Reduces Autoantibodies, Normalizes Low Complement, and Reduces Select B-Cell Populations in Patients With Systemic Lupus Erythematosus




To assess the effects of the B-lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B- and T-cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.


Pooled data from two phase 3 trials—BLISS-52 and -76—comparing belimumab 1 or 10 mg/kg vs placebo (each plus standard SLE therapy) were analyzed for changes in autoantibodies, immunoglobulin (Ig), and complement (C); BLISS-76 patients were analyzed for changes in B- and T-cell populations, and effects on prior vaccine-induced antibody levels.


Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies, and improvement in C3/C4, resulting in greater positive-to-negative conversion rates for IgG anti–double-stranded DNA (anti-dsDNA), anti-Smith, anticardiolipin, and antiribosomal P autoantibodies, and normalization of hypergammaglobulinemia and low C3/C4. Belimumab-treated patients experienced significant decreases in naïve and activated B cells, as well as plasma cells, whereas memory B cells and T-cell populations did not decrease. Belimumab did not substantially affect pre-existing antipneumococcal or antitetanus antibody levels. Post-hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P ≤ 0.01) who were anti-dsDNA positive with low C3/C4 at baseline. Normalization of C3 or anti-dsDNA by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.


Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B-cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with considerable morbidity, increased mortality, and poor health-related quality of life (1,2). Immunologic features of SLE include abnormal activation of B- and T-cell lymphocytes, and elevated titers of autoantibodies (3,4).

B-lymphocyte stimulator (BLyS) is a 285-amino acid type-II protein member of the tumor necrosis factor ligand superfamily (5,6). In vitro and in vivo studies have demonstrated BLyS to be a vital B-cell survival factor (79), with important roles in the differentiation of immature to mature B cells (10,11), and immunoglobulin (Ig) class switching and production (12,13).

There is a strong connection between BLyS and SLE. In mice that otherwise are not autoimmune-prone, constitutive overexpression of BLyS leads to SLE-like disease (1416). In human SLE, circulating BLyS levels are elevated in as many as 50% of patients (17,18), and a large 2-year longitudinal study documented a significant correlation between BLyS levels and clinical disease activity (19).

Belimumab is a human IgG1λ monoclonal antibody that inhibits B-cell survival and differentiation by neutralizing soluble BLyS, without directly causing B-cell death (20,21). Two international phase 3 trials—BLISS-52 and BLISS-76 (ClinicalTrials.gov identifiers NCT00424476 and NCT00410384, respectively)—evaluated the safety and efficacy of belimumab in patients with autoantibody-positive (“seropositive”) SLE (defined as a serum antinuclear antibody [ANA] titer of ≥1:80 and/or a positive serum anti–double-stranded DNA [anti-dsDNA] test) (22,23). Both trials showed that belimumab 10 mg/kg plus standard SLE therapy was generally well tolerated and met the primary endpoint of a significantly improved SLE Responder Index (SRI) at week 52 compared with standard therapy alone. Several SLE studies have suggested that assessment of immunologic biomarkers, such as anti-dsDNA and complement (C), may be useful in predicting disease activity, the occurrence of flares, and the response to treatment (2427). The present study focused on the effects of belimumab treatment in BLISS-52 and BLISS-76 on biomarkers, including serum Ig, autoantibodies, C components, and select B- and T-cell populations; biomarkers as predictors of treatment response; and the ability of patients treated with belimumab to maintain antipneumococcal and antitetanus titers from vaccinations received prior to study entry.


Study design

BLISS-52 (N = 865) and BLISS-76 (N = 819) were randomized, double-blind, placebo-controlled, multicenter trials comparing belimumab 1 and 10 mg/kg with placebo, all plus standard therapy, in patients with active SLE. The trials had similar designs, which were described in detail previously (22,23). In brief, all patients had a Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at screening, were autoantibody-positive (ANA ≥1:80 or anti-dsDNA ≥30 IU/mL), and had received stable, standard therapy for ≥30 days prior to the specific study. Patients received belimumab or placebo via intravenous infusion on days 0, 14, and 28, and then every 28 days through week 48 (BLISS-52) or 72 (BLISS-76), plus standard therapy throughout the entire studies. Patients had progressive restrictions on concurrent immunosuppressive and antimalarial medications, and on prednisone during the trials. The primary endpoint in both trials was 52-week response rate as assessed by SRI (defined as ≥4-point improvement in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group A organ domain score and no more than 1 new B score, and no worsening [<0.3-point increase] in Physician’s Global Assessment score) (28).

Biomarker analyses

Since the changes in biomarkers in the BLISS-52 and BLISS-76 trials through week 52 (conclusion of BLISS-52) were similar (data not shown), and each trial had the same basic clinical design and met its primary endpoint, the results were pooled to increase the power to detect the belimumab treatment effect and present a more representative overall effect of biomarker changes observed in a subgroup of patients. Presence of biomarkers at baseline was recorded to evaluate its relation to overall treatment effect, as measured by SRI and SLE flares.

Details on the methods of measurement of some biomarkers (ie, IgG, IgM, IgA, C3, C4, anti-dsDNA, and ANA) in BLISS-52 and BLISS-76 were reported previously (22,23). Other biomarkers analyzed in both studies included anti-Smith (Sm), anticardiolipin (aCL), and antiribosomal P autoantibodies, which were measured by enzyme-linked immunosorbent assay. All autoantibodies evaluated were for IgG subtypes, except aCL, which was assessed by IgG, IgM, and IgA subtypes. Changes in B- and T-cell subsets were analyzed only in BLISS-76 and are presented through week 76. B-cell subsets consisted of CD20+ and activated (CD20+CD69+), memory (CD20+CD27+), and naïve (CD20+CD27) subsets, and plasma cell subsets consisted of plasmacytoid (CD20+CD138+), plasma (CD20CD138+), short-lived plasma (CD20CD27Bright [BR]), and SLE (CD19+CD27BRCD38BR) subsets. (Note: BR indicates high levels of expression of this cell surface marker. (29,30)) T-cell subsets consisted of CD3+CD4+ and CD3+CD8+ subsets. Complement and anti-dsDNA were measured at baseline and every 4 weeks through week 52. All other autoantibodies were measured at baseline and week 52. In BLISS-76, immunoglobulins were measured at baseline, every 8 weeks through week 40, and week 52. In BLISS-52, IgG was measured at baseline and weeks 8, 24, 40, and 52, and IgM and IgA were measured at baseline and week 52. B- and T-cell subsets were measured only in BLISS-76 at baseline, and weeks 8, 24, 52, and 76.

Vaccine substudy

A substudy of BLISS-76 assessed the effects of belimumab on vaccine-associated antibody levels in patients receiving pneumococcal or tetanus vaccine within 5 years. Antibody levels were measured at baseline and week 52 using multi-analyte immune detection (lower limit of quantitation: 0.3 mg/mL) for the 7 type-specific pneumococcal polysaccharide antigens included in the 12-valent conjugate vaccines, ie, 1, 3, 4, 8, 9(9N), 12(12F), 14, 19(19A), 23(23F), 26(26B), 51(7F), and 56(18C) (31). Enzyme-linked immunosorbent assay was used to measure antitetanus toxoid; based on the reported protective levels of 0.10 IU/mL (32), antitoxoid IgG levels ≥0.50 IU/mL were conservatively considered to be protective on this platform.

Statistical analysis

Percent changes in biomarkers were compared between the placebo group and belimumab groups using the Wilcoxon rank-sum test. The proportions of patients who normalized their biomarkers or maintained antibody levels in the placebo vs belimumab groups were compared using the likelihood ratio chi-square test. When >20% of the expected contingency table cell counts were <5, the proportion of patients who maintained antibody levels was analyzed using Fisher’s exact test. Among patients with elevated BLyS at baseline and those with low C3 or C4 and positive for anti-dsDNA at baseline, the SRI response rate at week 52 was compared between the placebo and belimumab treatment groups using a logistic-regression model. Time to first severe flare was compared between the placebo and belimumab groups using Cox proportional hazards model. Both analyses were adjusted for baseline randomization factors. The association of biomarker normalization with SRI response and SLE flare was assessed using the likelihood ratio test and the log-rank test, respectively. The association analysis was performed in all patients combined and in belimumab-treated patients separately.


Serologic biomarkers

Baseline demographic and biomarker values in the 2 studies are presented in Table 1.

Table 1
Baseline demographics, disease characteristics, and biomarker levels in BLISS-52 and -76, and baseline median B- and T-cell values in BLISS-76.*

Improvements in IgG levels were significantly greater with belimumab 1 and 10 mg/kg than with placebo by week 8 and remained significantly greater through week 52 (median % reductions: 13.8% and 15.3% vs 2.5%, respectively; P <0.001; Figure 1A and Table 2). In addition, belimumab reduced autoantibody levels, and significantly more patients treated with belimumab converted from positive to negative status for anti-dsDNA (both doses), anti-Sm (10 mg/kg), antiribosomal P (10 mg/kg), and aCL-IgG (both doses) autoantibodies by week 52 (Table 2 and Figure 1B). Of note, belimumab 1- and 10-mg/kg treatment resulted in significantly lower anti-dsDNA levels than did placebo as early as week 8 and at every measurement thereafter (median percent reductions at week 52: 36.6% and 40.8%, respectively, vs 10.2%; P <0.001), and the median percent reduction in anti-dsDNA IgG among anti-dsDNA–positive patients on belimumab was >2-fold more than the reduction in overall IgG among all patients on belimumab (Figure 1A and Table 2).

Figure 1
Effects of belimumab treatment on autoantibodies, immunoglobulin (Ig), and complement (C) at week 52 (pooled data). A, changes in IgG in all patients and in anti–double-stranded DNA (anti-dsDNA) in patients positive at baseline. B, rates of conversion ...
Table 2
Changes from baseline in immunoglobulins, autoantibodies, and biomarker predictors of SRI and severe flare reduction: pooled data.

C3 and C4 levels increased in patients treated with belimumab. Among patients with low C3 or C4 levels at baseline, significant increases were observed with belimumab as early as week 4 and were maintained through week 52 (Figure 1C). Normalization of low C3 or C4 levels and hypergammaglobulinemia (IgG ≥16.2 g/L) at baseline occurred in significantly more patients with belimumab 1 and 10 mg/kg vs placebo (Figure 1D). Of note, patients with low C3 or C4 levels at baseline had greater improvements in these levels with the higher belimumab dose. Grade 3 hypogammaglobulinemia (<400 ng/dL) was rare (no grade 4 reported) during therapy, with 1 patient each in the placebo and belimumab 10-mg/kg groups.

Overall, belimumab-treated patients experienced lower rates of worsening of biomarkers than did placebo-treated patients who received standard therapy alone (Table 2). Conversion from anti-dsDNA negative to positive was infrequent and occurred significantly more often in patients with placebo than with belimumab 10 mg/kg (P = 0.02). Conversion from normal to low C3/C4 levels also occurred more often in patients treated with placebo than in those treated with belimumab 1 mg/kg (P = NS/<0.001) or 10 mg/kg (P <0.001/= 0.002). Among patients with normal levels of IgG at baseline, more patients treated with placebo developed IgG hypergammaglobulinemia than did those treated with either dose of belimumab (P <0.001).

Effects on lymphocytes

In BLISS-76, belimumab treatment significantly reduced median levels of CD20+ B cells through week 76 (55%–58%; P <0.001), while preserving memory B cells and T-cell populations (Figures 2A and and3).3). Median reductions in naïve (CD20+CD27) B cells were significantly greater with either belimumab dose by week 8 and through week 76 than with placebo, while significant reductions in activated (CD20+CD69+) cells were observed with belimumab 10 mg/kg at week 52 and either dose at week 76 (Figure 2A). Both belimumab doses significantly reduced plasmacytoid (CD20+CD138+) cells by week 24 and were sustained through week 76. The effects of belimumab on CD20CD138+, CD20CD27BR, and CD19+CD27BRCD38BR plasma cell subsets appeared to be dose related, with significant reductions observed with 10 mg/kg by week 8 and maintained through week 76 (Figure 2B). There was a significant increase in memory (CD20+CD27+) B cells with belimumab, which was not dose dependent, and peaked at week 8 and gradually returned towards baseline thereafter.

Figure 2
Median percent changes in (A) B-cell subsets and (B) plasma cell subsets through week 76 in BLISS-76. SLE = systemic lupus erythematosus. * P <0.05; + P <0.01; # P <0.001.
Figure 3
Changes in T-cell values at weeks 52 and 76 in BLISS-76. BL = baseline.

There were no decreases observed in median CD3+, CD3+CD4+, or CD3+CD8+ T-cell counts between belimumab and placebo at week 52 or 76 (Figure 3). There was a modest, although not statistically significant, expansion (10%–15%) of CD3+CD4+ and CD3+CD8+ cells between baseline and week 52 in patients with belimumab, but no differences were apparent in CD4+CD8+ ratio at week 52 across all treatment groups.

Vaccine substudy

Effects on pre-existing vaccine antigen-specific antibody levels were assessed in patients who had received pneumococcal or tetanus vaccine within 5 years of the start of treatment in BLISS-76. In all, 26 patients with placebo, 28 with belimumab 1 mg/kg, and 22 with belimumab 10 mg/kg were evaluated for antipneumococcal IgG levels; the corresponding numbers were 33, 33, and 25 for antitetanus toxin IgG. Of the 6 serotypes reported by the CDC as causing the most frequent drug-resistant pneumococcal infection in the US (31), 5 correspond to serotypes tested in this study. At week 52, there were no significant differences across treatment groups in the percentages of patients maintaining antipneumococcal IgG titers to these 5 serotypes (Table 3); of the 7 additional pneumococcal vaccine serotypes tested, significantly lower titers were noted only for serotype 12F (data not shown). Antitetanus toxin IgG titers were not significantly decreased (Table 3). These changes from baseline in antitetanus and antipneumococcal IgG titers did not significantly alter the proportions of patients who maintained detectable titers for these vaccinations (data not shown).

Table 3
Percent change in pre-existing pneumococcal and tetanus titers from baseline to week 52.*

Clinical correlations with biomarker status at baseline and biomarker changes during the study

A post-hoc analysis was performed of pooled data from the two trials to investigate whether the ultimate clinical response correlated with BLyS level, autoantibody profile, or presence of low C levels at baseline. It was also assessed whether reduction of serum autoantibodies to normal levels or normalization of C levels during the course of the trials was accompanied by clinical benefit.

Detectable BLyS levels were observed in 98% of patients at baseline (Table 2). There was no correlation of baseline BLyS levels (quartiles) with SRI response at week 52 irrespective of therapy. Among the 287, 284, and 305 patients on placebo, and belimumab 1 and 10 mg/kg, respectively, who had low C3 or C4 and were anti-dsDNA positive at baseline, SRI rates at week 52 were significantly higher with belimumab 1 mg/kg (41.5%; P = 0.002) and 10 mg/kg (51.5%; P <0.001) than with placebo (31.7%). Further, risk of a severe flare (as assessed by the SELENA-SLEDAI Flare Index) was reduced with belimumab 1 mg/kg (20.4%; hazard ratio 0.67; P = 0.02) and belimumab 10 mg/kg (19.0%; 0.61; P = 0.004) vs placebo (29.6%). A modified SRI analysis that did not count normalization of anti-dsDNA or low complement in the calculation of a ≥4-point improvement in SELENA-SLEDAI score demonstrated that the differential SRI response with belimumab vs placebo was maintained in patients who were anti-dsDNA positive and had low complement levels at baseline, as well as in all patients (data not shown) irrespective of normalization of these biomarkers.

Biomarker changes while on therapy during the trials were explored as potential predictors of improvement in SRI or reduction of severe flares. Based on the modified SRI, evaluating all patients (irrespective of therapy), those with normalization of C4 had significantly greater response rates than those without normalization at week 4 (52% vs 41%; P = 0.02), week 28 (54% vs 42%; P <0.01), and thereafter (except for weeks 36 and 44). Among belimumab-treated patients only, modified SRI response rates were significantly greater in those with normalization of C4 than in those without normalization at week 4 (56% vs 44%; P = 0.02), week 16 (54% vs 45%; P <0.05), and week 28 (59% vs 43%; P <0.001), and thereafter (except for week 44). Patients with normalization of IgG, irrespective of treatment, had significantly greater SRI response rates than patients without normalization at week 24 (65% vs 50%; P <0.001), week 40 (69% vs 54%; P <0.001), and week 52 (66% vs 57%; P = 0.049). Belimumab-treated patients with normalization of IgG had significantly greater SRI response rates than patients without normalization at week 24 (69% vs 53%; P = 0.002) and week 40 (71% vs 56%; P = 0.002). Risk of severe flare was significantly lower in all patients (irrespective of therapy) with early normalization of C3 at week 4 (19% vs 27% in the non-normalized group; P = 0.04) and week 8 (17% vs 27%; P = 0.02), and of anti-dsDNA at week 8 (11% vs 22%; P = 0.04). In patients treated with belimumab, risk of severe flare was numerically lower with early normalization at week 8 of C3 (16% vs 24%; P = 0.08) and of anti-dsDNA (10% vs 19%; P = 0.12).

Changes over 52 weeks in B-cell and plasma cell subsets (measured in BLISS-76 only) were evaluated by quartile or absolute minimum % change from baseline to determine if B- or plasma cell reduction on therapy correlated with SRI response or reduction in severe SLE flare rate. Only the naïve B-cell subset, irrespective of therapy, showed a consistent association of greater % reduction from baseline with greater likelihood of SRI response at week 52 (all patients: 60.2% vs 46.0% SRI response rate with >70% [n = 171] vs ≤70% reduction [n = 361]; P = 0.002) and lower risk of severe flare over 52 weeks (7.6% vs 14.7% risk with >70% vs ≤70% reduction; P = 0.02).


Belimumab treatment combined with standard therapy (corticosteroids, immunosuppressives, and/or antimalarials) led to significant sustained reductions in autoantibody levels, and increases in C3 and C4 levels over 52 weeks compared with placebo plus standard therapy in patients with autoantibody-positive SLE. Significantly more patients treated with belimumab had normalization of high IgG levels, conversion from low to normal/high C3 and C4 levels, and conversion from positive to negative status for anti-dsDNA. In addition, treatment with belimumab 10 mg/kg resulted in significantly greater rates of conversion to negative status for anti-Sm, aCL IgG, and antiribosomal P autoantibodies. Treatment with belimumab 1 or 10 mg/kg was associated with significant reductions in CD20+ B cells and in multiple B- and plasma cell subsets, including naïve and activated B cells, as well as in CD20+/CD138+ plasma cell precursors (plasmablasts), while preserving the memory B-cell subset and T cells. Increases in plasma cell subsets have been associated with increased SLE disease activity (29). It is, therefore, noteworthy that in the present study, plasma cell subsets decreased in a dose-dependent manner with belimumab treatment and were significant with the 10-mg/kg dose compared with standard therapy alone. These collective results are in accordance with those from a study of the phase 2 clinical trial of belimumab (30,33), and are consistent with the mechanism of action of belimumab as an antibody that specifically targets and inhibits the activity of soluble BLyS.

In line with the preservation of memory B cells and T cells, belimumab treatment did not result in a significant reduction in pre-existing antibodies to pneumococcal and tetanus vaccines. Preservation of memory B cells appears to be due to their lack of dependence on BLyS for survival (34). The initial expansion of memory B cells in the blood (peaking at week 8 and then gradually returning to baseline) may be secondary to their release from disrupted germinal centers where these B cells reside, may be due to inhibition of their return to these lymphoid tissues, or may be consequent to promotion of differentiation of naïve B cells to memory B cells (21,33,35). In any case, similar percentages of patients with belimumab and placebo maintained specific antivaccine antibody titers at week 52, including those against 5 of the 6 serotypes (ie, 6B, 9V, 14, 19F, and 23F; the 6B and 9V serotypes overlap with 26B and 9N reported here) that most frequently cause invasive drug-resistant pneumococcal infection in the United States (31). In the BLISS studies, there were similar rates of serious and/or severe infections in the belimumab-treated groups compared with those treated with standard therapy alone (22,23). Taken together, these results suggest that belimumab treatment does not compromise the immune response to infection.

The post-hoc analyses pointed to likely meaningful correlations between biomarker changes and SRI response and/or incidence of severe flares. Normalization of C4 as early as treatment week 4 and at other times was correlated with increased SRI response in all patients, as well as in those treated with belimumab, regardless of whether normalization of low C levels or anti-dsDNA was counted in the calculation of improvement in SELENA-SLEDAI score. In addition, analysis of biomarker changes in all patients, as well as in those treated with belimumab, demonstrated that early normalization of C3 or anti-dsDNA was a predictor of reduced risk of severe flares. These results are in accordance with those of previous studies that suggested a correlation between anti-dsDNA positivity and low C levels on the one hand with increased disease activity and risk for flares on the other (24,27). In addition, SLE patients with >70% reductions in naïve B-cell populations, irrespective of therapy, had a greater likelihood of achieving an SRI response or having a lower incidence of severe flares. The naïve B-cell subset had the greatest % reductions with belimumab therapy of all B- and plasma cell subsets evaluated in BLISS-76.

In a phase 2 trial of belimumab in patients with SLE, belimumab was not associated with a significant benefit in improving SELENA-SLEDAI scores compared with placebo (33). Exploratory analyses in that study showed that belimumab was associated with a significant benefit in improving SELENA-SLEDAI scores in patients with serologic activity (ANA titer ≥1:80 or anti-dsDNA >30 IU/mL), providing the rationale for phase 3 testing in and enriching for patients with serologically active SLE. A post-hoc analysis in the BLISS studies showed significantly higher SRI rates and reduced risk of severe SLE flares in belimumab-treated patients who had low C3 or C4 levels and anti-dsDNA–positive status at baseline. This is consistent with the correlation of higher serologic activity with higher BLyS levels (>98% of patients had detectable BLyS in the two BLISS studies), which may permit autoantibody-producing cells to survive and continue producing autoantibodies. Furthermore, the median percent reduction in anti-dsDNA IgG among anti-dsDNA–positive patients was >2-fold greater than that in overall IgG among all patients treated with belimumab, which suggests that the effects of belimumab on autoantibody-producing cells may have been disproportionately greater than the effects on non-autoantibody–producing cells.

Higher BLyS levels at baseline did not correlate with a greater SRI response. Although higher serologic activity was associated with a better response to belimumab, the SRI response was not driven by normalization of anti-dsDNA or low complement, as the magnitude of treatment effect was similar in patients with and without normalization of these serologic parameters. These findings suggest that the efficacy of belimumab is greatest in SLE patients with high disease and serologic activity.


Supported by Human Genome Sciences, Inc., Rockville, Maryland, and GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom. Editorial support was provided by Matt Stenger, Eleanore Gross, and Geoff Marx of BioScience Communications, New York, New York, and was funded by Human Genome Sciences and GlaxoSmithKline.

Supported in part by NIH grant M01-RR-00043 to the General Clinical Research Center at the University of Southern California Keck School of Medicine.


ClinicalTrials.gov identifiers NCT00424476 and NCT00410384.


All authors were involved in drafting the article or revising it critically for important intellectual content and approved the final version submitted for publication. Dr Stohl had full access to all of the data in the studies, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. L Pineda, T-S Migone, ZJ Zhong, WW Freimuth.

Acquisition of data. W Stohl, F Hiepe, M Thomas, MA Scheinberg, A Clarke, C Aranow, FR Wellborne, C Abud-Mendoza, DR Hough, L Pineda, T-S Migone, ZJ Zhong, WW Freimuth, WW Chatham.

Analysis and interpretation of data. W Stohl, F Hiepe, KM Latinis, MA Scheinberg, A Clarke, C Aranow, C Abud-Mendoza, DR Hough, L Pineda, T-S Migone, ZJ Zhong, WW Freimuth, WW Chatham.

Drafting or revising the article. W Stohl, F Hiepe, KM Latinis, M Thomas, MA Scheinberg, A Clarke, C Aranow, FR Wellborne, C Abud-Mendoza, DR Hough, L Pineda, T-S Migone, ZJ Zhong, WW Freimuth, WW Chatham.

Final approval of the published article. W Stohl, F Hiepe, KM Latinis, M Thomas, MA Scheinberg, A Clarke, C Aranow, FR Wellborne, C Abud-Mendoza, DR Hough, L Pineda, T-S Migone, ZJ Zhong, WW Freimuth, WW Chatham.

Medical monitor. WW Freimuth.

Dr Stohl has received clinical trials support from Human Genome Sciences (HGS). Dr Hiepe has received consultancy fees from HGS and GlaxoSmithKline (GSK). Dr Latinis has received fees for consultancy and speaker’s bureau participation from HGS and GSK. Dr Clarke has received research support and consultancy fees from HGS and GSK, and clinical trials support from HGS. Dr Aranow has received consultancy fees from HGS. Dr Wellborne has received research support from HGS, and consultancy fees from HGS and GSK. Drs Hough, Pineda, Migone, Zhong, and Freimuth are employed by and own stock in HGS. The other authors declare that they have no conflicts of interest.


1. Lau CS, Mak A. The socioeconomic burden of SLE. Nat Rev Rheumatol. 2009;5:400–4. [PubMed]
2. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358:929–39. [PubMed]
3. Arbuckle MR, McClain M, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–33. [PubMed]
4. Muñoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, et al. SLE—a disease of clearance deficiency? Rheumatology. 2005;44:1101–7. [PubMed]
5. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3. [PubMed]
6. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer J, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56. [PMC free article] [PubMed]
7. Thompson JS, Schneider P, Kalled SL, Wang L, Lefevre EA, Cachero TG, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J Exp Med. 2000;192:129–35. [PMC free article] [PubMed]
8. Do RKG, Hatada E, Lee H, Tourigny MR, Hilbert D, Chen-Kiang S. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med. 2000;192:953–64. [PMC free article] [PubMed]
9. Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. 2000;192:1453–65. [PMC free article] [PubMed]
10. Rolink AG, Tschopp J, Schneider P, Melchers F. BAFF is a survival and maturation factor for mouse B cells. Eur J Immunol. 2002;32:2004–10. [PubMed]
11. Tardivel A, Tinel A, Lens S, Steiner QG, Sauberli E, Wilson A, et al. The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF. Eur J Immunol. 2004;34:509–18. [PubMed]
12. Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med. 2005;201:35–9. [PMC free article] [PubMed]
13. Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol. 2002;3:822–9. [PubMed]
14. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–9. [PubMed]
15. Khare SD, Sarosi I, Xia X-Z, McCabe S, Miner K, Solovyev I, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci U S A. 2000;97:3370–5. [PMC free article] [PubMed]
16. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–1710. [PMC free article] [PubMed]
17. 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;44:1313–9. [PubMed]
18. Zhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessler BJ, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10. [PubMed]
19. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58:2453–9. [PubMed]
20. Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, 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. [PubMed]
21. Halpern WG, Lappin P, Zanardi T, Cai W, Corcoran M, Zhong J, et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicol Sci. 2006;91:586–99. [PubMed]
22. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, et al. BLISS-76 Study Group. 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. [PubMed]
23. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled phase 3 trial. Lancet. 2011;377:721–31. [PubMed]
24. Petri M, Singh S, Tesfasyone H, Malik A. Prevalence of flare and influence of demographic and serologic factors on flare risk in systemic lupus erythematosus: a prospective study. J Rheumatol. 2009;36:2476–80. [PubMed]
25. Schur PH, Sandson J. Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med. 1968;278:533–8. [PubMed]
26. ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum. 1990;33:634–43. [PubMed]
27. Tseng CE, Buyon JP, Kim M, Belmont HM, Mackay M, Diamond B, et al. The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006;54:3623–32. [PubMed]
28. Furie R, Petri M, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61:1143–51. [PMC free article] [PubMed]
29. Jacobi AM, Odendahl N, Reiter K, Bruns A, Burmester GR, Radbruch A, et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48:1332–42. [PubMed]
30. Jacobi AM, Huang W, Wang T, Freimuth W, Sanz I, Furie R, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2010;62:201–10. [PMC free article] [PubMed]
31. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the advisory committee on immunization practices (ACIP) [Accessed February 11, 2011];MMWR. 1997 46(RR-08):1–24. at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00047135.htm. [PubMed]
32. Atkinson W, Wolfe S, Hamborsky J, editors. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. 12. Washington DC: Public Health Foundation; 2011.
33. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, et al. A phase II, randomized, double-blind, placebo controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61:1168–78. [PMC free article] [PubMed]
34. Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180:3655–9. [PubMed]
35. Badr G, Borhis G, Lefevre EA, Chaoul N, Deshayes F, Dessirier V, et al. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells. Blood. 2008;111:2744–54. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...