BioDrugs (2014) 28:211–228
DOI 10.1007/s40259-013-0074-x
SYSTEMATIC REVIEW
Efficacy and Safety of Biologic Therapies for Systemic Lupus
Erythematosus Treatment: Systematic Review and Meta-Analysis
Helena Hiemisch Lobo Borba • Astrid Wiens •
Thais Teles de Souza • Cassyano Januário Correr
Roberto Pontarolo
Published online: 5 November 2013
Ó Springer International Publishing Switzerland 2013
Abstract
Objectives The objectives of this study were to evaluate
the efficacy, safety, and tolerability of biologic drugs
compared with placebo for systemic lupus erythematosus
(SLE) treatment.
Methods A systematic review evaluating the efficacy and
safety of biologic therapies compared with placebo in adult
SLE patients treatment was performed. Data from studies
performed before September 2013 were collected from
several databases (MEDLINE, Cochrane Library, SCIELO,
Scopus, and International Pharmaceutical Abstracts). Study
eligibility criteria included randomized, double-blind, pla-
cebo-controlled trials; regarding treatment with biologic
agents in SLE adult patients; and published in English,
German, Portuguese, and Spanish. Extracted data were
statistically analyzed in a meta-analysis using the Review
Manager (RevMan) 5.1 software. Efficacy outcomes
included the SELENA-SLEDAI (Safety of Estrogens in
Lupus Erythematosus National Assessment version of the
SLE Disease Activity Index) score, the SRI (Systemic
H. H. L. Borba
A. Wiens
T. T. de Souza

C. J. Correr
R. Pontarolo (&)
Departamento de Farmácia, Universidade Federal do Paraná,
Campus III, Av. Pref. Lothário Meissner, 632, Jardim Botânico,
Curitiba, PR CEP 80210-170, Brazil
e-mail: pontarolo@ufpr.br
H. H. L. Borba
e-mail: helena.hlb@gmail.com
A. Wiens
e-mail: astridwiens@hotmail.com
T. T. de Souza
e-mail: thaisteles1@hotmail.com
C. J. Correr
e-mail: cassyano@ufpr.br
•
Lupus Erythematosus Responder Index), normalization of
low C3 (\90 mg/dL), anti-double-stranded DNA positive
to negative, and no new BILAG (British Isles Lupus
Assessment Group index) 1A or 2B flares. Data on safety
profile included adverse events, serious and severe adverse
events, death, malignancy, infections, and infusion reac-
tions. We also evaluated withdrawals from treatment due to
lack of efficacy or adverse events.
Results Thirteen randomized placebo-controlled trials
met the criteria for data extraction for systematic review. A
meta-analysis regarding the efficacy and safety of beli-
mumab compared with placebo involving four of these
trials was undertaken and the remainder contributed to a
meta-analysis of the safety of biologic agents. In addition,
two trials allowed the performance of a meta-analysis
regarding the efficacy and safety of rituximab compared
with placebo. Belimumab was more effective than placebo
in most evaluated outcomes. No significant differences in
the safety and tolerability data were observed between the
belimumab and placebo groups. No differences were
observed between the rituximab and placebo groups for the
efficacy outcomes or safety parameters. Extracted data
from the 13 studies were pooled, allowing assessment of
the safety of biologic drugs. The meta-analysis revealed a
satisfactory safety profile of these agents when used for
SLE treatment, as there were no significant differences
between the two evaluated groups (biologic agents and
placebo) for all outcomes analyzed.
Conclusion Belimumab exhibited a satisfactory profile
regarding efficacy, safety, and tolerability. Rituximab
showed no superiority over placebo in terms of efficacy,
despite its suitable safety profile. Biologic agents exhibited
a good safety profile for SLE treatment, indicating that
these agents are promising therapies and should be further
investigated.
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1 Introduction
Systemic lupus erythematosus (SLE) is a chronic rheu-
matic and autoimmune disease that affects approximately
ten times more women than men [1]. Although the causes
of SLE remain unclear, it is known that genetic, environ-
mental, and hormonal factors contribute to disease devel-
opment and that the presence of autoantibodies directed
against the cell nuclei is the main immunologic charac-
teristic of the disease [2].
Based on scientific progress and improvements in the
understanding of SLE pathogenesis, new therapeutic
approaches for SLE treatment have recently been proposed
[3]. These approaches represent a breakthrough in SLE drug
therapy because conventional treatments such as hydroxy-
chloroquine, corticosteroids, and cyclophosphamide may
produce serious adverse events including blindness, osteo-
porosis, and infertility, respectively [4, 5]. Many of the new
drugs under investigation for SLE treatment are categorized as
immunobiologicals. These biologic agents are members of
various therapeutic classes such as inflammatory cytokine
inhibitors, agents that act on B cells, co-stimulatory blockers,
and complement inhibitors [3]. These drugs, although prom-
ising, are very expensive; thus, it is necessary to think care-
fully about their availability to a population.
The biologic drug belimumab has been approved by the
US FDA for the treatment of adults with SLE who are
receiving standard therapy and present both an autoanti-
body-positive and active SLE [3, 6]. Belimumab is a fully
humanized antibody that inhibits B cells by binding to the
B-lymphocyte stimulator (BLyS) to block its biological
activity. BLyS promotes the survival, differentiation, and
activity of B cells [7], and belimumab reduces the activa-
tion of the immune system by inhibiting B cells, which
decreases disease activity [8].
Among the newly developed treatments for SLE, only
belimumab has been approved. Thus, it is important to
investigate the efficacy and safety of this drug and the other
biologic agents that are also potential therapeutic options
for SLE treatment. To evaluate the efficacy and safety
profile of biologic agents, compared with placebo, in adult
patients with SLE, a systematic review of randomized
clinical trials was conducted, and the extracted data were
statistically analyzed by meta-analysis.
2 Methods
We conducted a systematic review and meta-analysis of
randomized controlled trials (RCTs) that compared bio-
logic therapies to placebo in adult SLE patients receiving
standard care (prednisone, antimalarial and immunosup-
pressive drugs). Trials without a placebo group, studies
H. H. L. Borba et al.
without clinical results, and articles that were only avail-
able as abstracts were excluded from the systematic review.
Two independent reviewers performed electronic sear-
ches of the following databases: MEDLINE, Cochrane
Library, SCIELO, Scopus, and International Pharmaceuti-
cal Abstracts. The following descriptors were used: SLE,
randomized, clinical trials, Etanercept, Adalimumab, Go-
limumab, Certolizumab pegol, Rituximab, Ocrelizumab,
Epratuzumab, Abetimus, Edratide, Belimumab, Atacicept,
Abatacept, Efalizumab, Sirolimus, Infliximab, Si-
falimumab, Rontalizumab, Anakinra, Tocilizumab, Ecu-
lizumab. Boolean operators such as ‘‘AND’’ and ‘‘OR’’
were also used in the electronic search. Search filters based
on language (English, German, Portuguese, and Spanish),
species (humans), and article types (clinical trials) were
used. The electronic searches were concluded in September
2013.
Two reviewers evaluated the selected studies for meth-
odological quality according to Cochrane Collaboration’s
tool for assessing the risk of bias described in the Cochrane
Handbook [9] and also applying the validated Jadad’s scale
[10]. Some bias such as inadequate blinding, absence of
incomplete data outcome-addressed description, or selec-
tive reporting may affect the evidence of the study. Thus,
these items should be investigated and classified as low or
high risk of bias [9]. Prepared tables were used for data
extraction, and a third reviewer was available to resolve
conflicting results between the first two reviewers. How-
ever, a third reviewer was not necessary in this study.
Efficacy was the primary outcome in the present study,
followed by safety. The measures used to evaluate efficacy,
all dichotomous variables [with the exception of rituximab,
for which two continuous outcomes were also analyzed—
time-adjusted area under the curve minus baseline (AUC-
MB) of the BILAG (British Isles Lupus Assessment Group
index) score, and change in SF-36 PCS (physical compo-
nent summary) score], were the SELENA-SLEDAI (Safety
of Estrogens in Lupus Erythematosus National Assessment
version of the SLE Disease Activity Index) score, the SRI
(Systemic Lupus Erythematosus Responder Index), nor-
malization of low C3 (\90 mg/dL), anti-double-stranded
DNA (dsDNA) positive to negative, and no new BILAG
1A or 2B flares. Data on safety included any adverse
events, serious adverse events (e.g., events that required
prolonged hospitalization, led to the risk of death, resulted
in death, or were considered to be serious by the author
[11]), severe adverse events (evaluated according to the
severity of the event), death, malignancy, infections, and
infusion reactions. We also evaluated withdrawals from
treatment due to lack of efficacy or adverse events.
Statistical analyses were performed using Review
Manager (RevMan) version 5.1 (The Nordic Cochrane
Centre, The Cochrane Collaboration, Copenhagen,
Biologic Therapies for SLE
Sweden). Risk ratios were chosen for effect measures using
the inverse variance model with a 95 % confidence interval
(random-effects model) for dichotomous variables.
Statistical heterogeneity among results was assessed
using the I2 statistic, which is easily interpreted. The I2
values are measured as a percentage that ranges from 0 to
100 %, and heterogeneity can be classified as low
(I2 \ 25 %), moderate (25 % \ I2 \ 50 %), or high
(I2 [ 50 %) [12].
Sensitivity analyses were performed to evaluate the
accuracy of the results. To check the heterogeneity effect,
the reviewers removed the included studies one by one to
verify changes in I2 values. This method allowed for the
identification of studies that were responsible for high
heterogeneity and further investigation of clinical and
methodological differences that may have contributed to
this effect. The random-effects model can correct statistical
heterogeneity and, therefore, removal of the studies that
contributed to high values of I2 from the meta-analysis was
not necessary.
3 Results
Our systematic review identified 611 articles in the elec-
tronic databases (59 MEDLINE, 24 Cochrane Library, 128
International Pharmaceutical Abstracts, 394 Scopus, 3
SCIELO, 3 manual search) (Fig. 1). Duplicate articles
(n = 119) were directly excluded. After reading the titles
and abstracts of the remaining 492 studies, 466 were
excluded based on the previously established inclusion
criteria. After that process, a full reading of the 26
remaining randomized clinical trials was performed, after
which 13 studies were excluded. At the end of the
screening, 13 studies (all randomized, double-blinded, and
placebo-controlled trials) were selected for the meta-ana-
lysis, and safety data of the biologic agents were extracted
[13–25]. All included studies presented moderate or high
quality (at least 3 points on the Jadad’s scale) and a low
risk of bias.
Belimumab and rituximab were the only biologic agents
for which it was possible to perform an individualized
meta-analysis regarding efficacy and safety. For the other
drugs, an efficacy evaluation was conducted based on the
results reported by each study individually. A safety meta-
analysis of all biologic agents grouped, with data extracted
from the 13 studies selected through the systematic review,
was also performed.
The studies that were included in the meta-analyses
documented the use of belimumab 1 and 10 mg/kg,
administered as an intravenous infusion on days 0, 14, 28,
and then every 28 days thereafter, as a single infusion, or
as two infusions separated by 21 days. Rituximab was
213
evaluated in a dose of 1,000 mg, administered intrave-
nously on days 1, 15, 168, and 182.
The baseline characteristics of patients included in the
selected studies are presented in Table 1, along with a brief
description of the respective biologic treatments.
3.1 Efficacy of Belimumab
The endpoints related to the efficacy of belimumab for the
treatment of SLE patients were divided into several sub-
groups for assessment. Figure 2 presents the meta-analysis
data from the randomized clinical trials using belimumab at
a dose of 1 mg/kg, and Fig. 3 presents the data from trials
using 10 mg/kg. For the final result of the meta-analysis,
we added some outcomes that were discussed in only one
study. These outcomes were not evaluated separately.
Our meta-analysis revealed significant results for the
efficacy of belimumab 1 mg/kg relative to control for SRI
at week 52, for a C4-point reduction in the SELENA-
SLEDAI score at week 52, for normalization of low C3
(\90 mg/dL) at week 52, for anti-dsDNA positive to
negative at week 52, and for no new BILAG 1A or 2B
flares at week 52. The results of the other efficacy
parameters between belimumab and placebo were not
significantly different, most likely due to the small number
of studies included. Nevertheless, this meta-analysis result
is favorable for belimumab treatment and suggests a
greater efficacy of this drug than placebo.
Statistical analyses revealed a high heterogeneity
(I2 = 60 %) between the studies for the efficacy outcomes
of belimumab 1 mg/kg. The sensitivity analysis revealed
that the study by Wallace et al. [22] was responsible for
this heterogeneity: once this study was removed from the
analysis, I2 values decreased to 33 %. What may have
contributed to the high heterogeneity is the fact that the
Wallace et al. [22] study is a phase II trial, whereas the
other included studies are phase III trials. Differences in
entry criteria as well as where studies were undertaken may
have played a role in the heterogeneity found in some of
the analyses.
Significant results were obtained with belimumab
10 mg/kg relative to placebo for the SRI at week 52, for a
C4-point reduction in the SELENA-SLEDAI score at
week 52, for normalization of low C3 at week 52, for anti-
dsDNA positive to negative at week 52, and for no new
BILAG 1A or 2B flares at week 52.
Statistical analysis revealed a high heterogeneity
(I2 = 78 %) between the studies for the efficacy outcomes
of belimumab 10 mg/kg. No single study was responsible
for this high heterogeneity. The removal of the Wallace
et al. [22] study from the meta-analysis revealed that this
study did not contribute to the high heterogeneity because
high values for I2 were maintained (I2 = 70 %). The
214
Fig. 1 PRISMA 2009 flowchart
for biologic agents in systemic
lupus erythematosus
randomized controlled trials.
RCTs randomized controlled
trials
reason for this heterogeneity is not known, but it was
similar to that observed for the meta-analysis of belimumab
1 mg/kg.
3.2 Safety of Belimumab
The safety results of treatments with belimumab 1 mg/kg
are presented in Fig. 4. These results are divided into any
adverse event, serious adverse events, severe adverse
events, death, malignancy, infections, and infusion reac-
tions. Figure 5 presents the safety results for treatments
with belimumab 10 mg/kg for the same parameters. The
tolerability of belimumab was assessed by examining
withdrawals due to lack of efficacy and adverse events.
Figure 6 presents these results for belimumab 1 mg/kg, and
Fig. 7 presents the data for belimumab 10 mg/kg.
Statistical analyses revealed an absence of heterogeneity
between the included studies for the safety outcomes for
both analyzed doses (belimumab 1 and 10 mg/kg), and an
I2 = 0 % was obtained. No significant differences between
the belimumab (1 and 10 mg/kg) and placebo groups were
observed. These results indicated that belimumab 1 and
10 mg/kg exhibited good safety profiles for SLE treatment.
Tolerability results also demonstrated that belimumab
was a suitable therapy for SLE because no significant
differences in withdrawals (due to lack of efficacy and to
adverse events) were observed between the belimumab (1
H. H. L. Borba et al.
and 10 mg/kg) and placebo groups. Statistical analyses
revealed no heterogeneity between the included studies
(I2 = 0 %) for the meta-analyses of belimumab 1 and
10 mg/kg.
3.3 Efficacy of Rituximab
The efficacy outcomes regarding rituximab included two
dichotomous variables (clinical response and BILAG C
score), and two continuous variables (time-adjusted
AUCMB of the BILAG score, and change in SF-36 PCS).
Table 2 presents the meta-analysis data from the two ran-
domized clinical trials using rituximab. Our results
showed no significant differences between the rituximab
group and the placebo group. Statistical analyses revealed
an absence of heterogeneity between the included studies
(I2 = 0 %).
3.4 Safety of Rituximab
The safety outcomes included serious adverse events,
infections, deaths, infusion reactions and withdrawal due to
adverse events. These results are presented in Table 3.
Statistical analyses revealed the absence of significant
differences between the rituximab group and placebo
group, indicating the good safety profile of this drug for
SLE treatment. An absence of heterogeneity among the
Table 1 Baseline characteristics of patients included in the selected studies
Study/treatment N Age (years) Previous Previous Previous SLE SELENA- SDI Anti-dsDNA ANA C 1:80 C3 B LLN C3 (mg/dL) C1 BILAG BILAG Index
(Jadad’s Score) ISS [N (%)] CE AM duration SLEDAI (IU/mL) [N (%)] [N (%)] A or B Global Score
[N (%)] [N (%)] (years) score (mean ± SD)
[N (%)]

Furie et al. [16], 2008 (3) Median Median Median Median ‡1:40
Belimumab IV 1 mg/kg 15 36 (22–56) NR 14 (93) NR 3.4 (0.4–13) 2 (0–6) NR 6.0 (4.0–65.5) 13 (87) NR NR NR NR
Belimumab IV 4 mg/kg 14 48.5 NR 9 (54) NR 8.7 0 (0–5) NR 4.5 (4.0–24.0) 14 (86) NR NR NR NR
Biologic Therapies for SLE

(23–62) (0.4–37.7)
Belimumab IV 10 mg/kg 14 37 (22–61) NR 10 (71) NR 6.3 2 (0–8) NR 27.0 13 (93) NR NR NR NR
(1.8–20.8) (4.0–257.0)
Belimumab IV 20 mg/kg 14 38.5 NR 8 (57) NR 8.0 2 (0–4) NR 5.0 13 (93) NR NR NR NR
(23–80) (0.3–29.4) (4.0–729.0)
Placebo 13 38 (30–58) NR 9 (69) NR 5.3 4 (0–4) NR 9.5 12 (92) NR NR NR NR
(0.4–15.3) (4.0–162.5)
Wallace et al. [22], 2009 (3)
Belimumab IV 1.0 mg/ 114 42.0 ± 11.7 52 (45.6) 78 (68.4) 80 (70.2) 8.5 ± 7.2 9.9 ± 0.4 NR NR 80 (70.2) NR 110.0 ± 3.6 109 (95.6) NR
kg days 0, 14, 28 and
then every 28 days for
52 weeks ? SOC
Belimumab IV 4.0 mg/ 111 42.6 ± 10.7 59 (53.2) 73 (65.8) 72 (64.9) 10.1 ± 9.2 9.4 ± 0.5 NR NR 82 (73.9) NR 109.4 ± 3.0 107 (96.4) NR
kg days 0, 14, 28 and
then every 28 days for
52 weeks ? SOC
Belimumab IV 10.0 mg/ 111 41.8 ± 11.7 58 (52.3) 74 (66.7) 77 (69.4) 8.5 ± 8.0 9.5 ± 0.4 NR NR 74 (66.7) NR 112.7 ± 3.5 108 (97.5) NR
kg days 0, 14, 28 and
then every 28 days for
52 weeks ? SOC
Placebo ? SOC 113 42.2 ± 10.9 55 (48.7) 82 (72.6) 84 (74.3) 8.1 ± 7.4 9.5 ± 0.5 NR NR 84 (74.3) NR 114.6 ± 3.4 102 (90.3) NR
Navarra et al. [21], 2011 (4)
Belimumab IV 1.0 mg/ 288 35.0 ± 10.6 120 (42) 276 (96) 195 (68) 5.0 ± 4.6 9.6 ± 3.8 NR 523.7 ± 875.7 272 (94) 148 (51) 0.90 ± 0.30 166 (58) NR
kg days 0, 14, 28 and (g/L)
then every 28 days for
48 weeks ? SOC
Belimumab IV 10.0 mg/ 290 35.4 ± 10.8 123 (42) 278 (96) 185 (64) 5.0 ± 5.1 10.0 ± 3.9 NR 603.7 ± 972.5 276 (95) 147 (51) 0.92 ± 0.32 172 (59) NR
kg days 0, 14, 28 and (g/L)
then every 28 days for
48 weeks ? SOC
Placebo 287 36.2 ± 11.8 122 (43) 276 (96) 201 (70) 5.9 ± 6.2 9.7 ± 3.6 NR 525.8 ± 851.9 264 (92) 132 (46) 0.94 ± 0.31 166 (58) NR
(g/L)
Furie et al. [17], 2011 (5)
Belimumab IV 1.0 mg/ 271 40.0 ± 11.4 153 (56.5) 211 171 7.9 ± 7.1 9.7 ± 3.7 1.0 ± 1.4 451 ± 748 256 (94.5) 100 (37) 995 ± 321 173 (63.8) NR
kg days 0, 14, 28 and (77.9) (63.1)
then every 28 days for
72 weeks ? SOC
Belimumab IV 10.0 mg/ 273 40.5 ± 11.1 148 (54.2) 200 168 72. ± 7.5 9.5 ± 3.6 1.0 ± 1.4 551 ± 911 245 (89.7) 115 (42) 973 ± 325 160 (58.6) NR
kg days 0, 14, 28 and (73.3) (61.5)
then every 28 days for
72 weeks ? SOC
215
Table 1 continued
216

Study/treatment N Age (years) Previous Previous Previous SLE SELENA- SDI Anti-dsDNA ANA C 1:80 C3 B LLN C3 (mg/dL) C1 BILAG BILAG Index
(Jadad’s Score) ISS [N (%)] CE AM duration SLEDAI (IU/mL) [N (%)] [N (%)] A or B Global Score
[N (%)] [N (%)] (years) score (mean ± SD)
[N (%)]

Placebo 275 40.0 ± 11.9 154 (56.0) 212 180 7.4 ± 6.7 9.8 ± 4.0 1.0 ± 1.5 556 ± 931 253 (92.0) 116 (42) 958 ± 303 187 (68.0) NR
(77.1) (65.5)
Furie et al. [15], 2001 (4)
Abetimus sodium IV 4 13 37.5 ± 10.6 NR 10 (77) NR 9.1 NR NR 374.3 ± 132.4 NR NR NR NR
1 mg monthly
Abetimus sodium IV 5 NR NR NR NR 91.3 ± 24.2 NR NR NR NR
1 mg biweekly
Abetimus sodium IV 4 NR NR NR NR 53.3 ± 92.0 NR NR NR NR
1 mg weekly
Abetimus sodium IV 5 18 41.4 ± 13.5 NR 13 (72) NR 9.1 NR NR 35.3 ± 118.4 NR NR NR NR
10 mg monthly
Abetimus sodium IV 7 NR NR NR NR 80.6 ± 22.1 NR NR NR NR
10 mg biweekly
Abetimus sodium IV 6 NR NR NR NR 61.5 ± 75.1 NR NR NR NR
10 mg weekly
Abetimus sodium IV 6 18 37.4 ± 9.9 NR 9 (50) NR NR NR 69.9 ± 108.1 NR NR NR NR
50 mg monthly
Abetimus sodium IV 7 NR NR NR NR 33.6 ± 20.5 NR NR NR NR
50 mg biweekly
Abetimus sodium IV 5 NR NR NR NR 179.5 ± 82.3 NR NR NR NR
50 mg weekly
Placebo monthly 3 9 39.1 ± 14.8 NR 9 (100) NR 10.7 NR NR 43.5 ± 152.9 NR NR NR NR
Placebo biweekly 3 NR NR NR NR 29.3 ± 31.3 NR NR NR NR
Placebo weekly 3 NR NR NR NR 27.1 ± 106.2 NR NR NR NR
Cardiel et al. [13], 2008/Linnik et al. [40], 2005 (3)
Abetimus sodium IV 145 37.1 ± 11 69 (48) 121 (83) NR 10.0 ± 7.69 NR NR 86.5 ± 137.1 NR NR 87.0 ± 25.4 NR NR
100 mg weekly
Placebo 153 35.2 ± 9.9 64 (42) 127 (83) NR 9.1 ± 6.91 NR NR 75.8 ± 69.3 NR NR 83.5 ± 28.2 NR NR
Dall’Era et al. [14], 2007 (3) Median
Atacicept SC 0.3 mg/kg 6 46.5 NR 18 (36) 29 (59) 9.6 2.0 (0–7) NR NR NR NR NR NR NR
single dose (23–64) (3.4–34.6)
Atacicept SC 1 mg/kg 6 35.0 NR 12.4 2.0 (0–8) NR NR NR NR NR NR NR
single dose (24–54) (0.4–36)
Atacicept SC 3 mg/kg 6 55.5 NR 12.3 1.0 (0–6) NR NR NR NR NR NR NR
single dose (44–63) (5.1–25.2)
Atacicept SC 9 mg/kg 6 41.0 NR 5.0 3.0 (2–8) NR NR NR NR NR NR NR
single dose (30–60) (0.8–46.5)
Atacicept SC 1 mg/kg 7 51.0 NR 16.8 2 (0–6) NR NR NR NR NR NR NR
weekly (26–64) (2.8–36.8)
Atacicept SC 3 mg/kg 6 42.5 NR 9.0 (5–27) 4 (0–6) NR NR NR NR NR NR NR
weekly (36–49)
Placebo single dose 8 43.5 NR 10.3 2.0 (0–7) NR NR NR NR NR NR NR
(26–61) (1.2–28.6)
H. H. L. Borba et al.
Table 1 continued
Study/treatment N Age (years) Previous Previous Previous SLE SELENA- SDI Anti-dsDNA ANA C 1:80 C3 B LLN C3 (mg/dL) C1 BILAG BILAG Index
(Jadad’s Score) ISS [N (%)] CE AM duration SLEDAI (IU/mL) [N (%)] [N (%)] A or B Global Score
[N (%)] [N (%)] (years) score (mean ± SD)
[N (%)]

Placebo weekly 4 59.0 NR 13.3 (6–26) 1 (0–6) NR NR NR NR NR NR NR

(42–63)
Merrill et al. [19], 2010b (4)
Biologic Therapies for SLE

Abatacept IV 10 mg/ 118 39.1 ± 12.4 97 (82.2) 117 83 (70.3) 7.2 ± 7.3 NR 0.5 ± 0.9 NR NR NR NR NR NR
kg ? prednisone days 1, (99.2)
15, 29 and then every
4 weeks
Placebo ? prednisone 57 37.6 ± 11.5 43 (75.4) 57 37 (64.9) 6.5 ± 6.0 NR 0.4 ± 0.7 NR NR NR NR NR NR
(100.0)
Merrill et al. [20], 2011 (4) Median
(months)
Sifalimumab IV 0.3 mg/ 6 47 ± 11 NR 0 (0) 3 (50) 159 5.3 (3.7) NR NR NR NR NR 2 (33) NR
kg single dose (25–313)
Sifalimumab IV 1.0 mg/ 6 42 ± 9 NR 1 (17) 5 (83) 43 (1–112) 7.3 (2.1) NR NR NR NR NR 5 (83) NR
kg single dose
Sifalimumab IV 3.0 mg/ 6 44 ± 7 NR 1 (17) 2 (33) 29 (16–196) 5.7 (2.7) NR NR NR NR NR 3 (50) NR
kg single dose
Sifalimumab IV 10.0 mg/ 7 46 ± 5 NR 4 (57) 5 (71) 17 (4–425) 3.9 (3.2) NR NR NR NR NR 2 (29) NR
kg single dose
Sifalimumab IV 30.0 mg/ 8 41 ± 18 NR 4 (50) 6 (75) 69 (1–258) 4.4 (3.1) NR NR NR NR NR 3 (38) NR
kg single dose
Placebo 17 48 ± 10 NR 2 (12) 13 (77) 94 (4–370) 5.4 (3.0) NR NR NR NR NR 8 (47) NR
Petri et al. [23], 2013 (4)
Sifalimumab IV 0.3 mg/kg 26 45.0 ± 11.6 NR 16 (61.5) 17 (65.4) NR 10.7 ± 5.7 NR NR 26 (100.0) 62 (512) NR 18 (69.2) NR
biweekly until 14 doses
Sifalimumab IV 1.0 mg/kg 25 41.6 ± 11.6 NR 20 (80.0) 17 (68.0) NR 10.4 ± 4.2 NR NR 25 (100.0) NR 16 (64.0) NR
biweekly until 14 doses
Sifalimumab IV 3.0 mg/kg 27 43.0 ± 11.2 NR 18 (66.7) 20 (74.1) NR 10.4 ± 4.6 NR NR 27 (100) NR 21 (77.8) NR
biweekly until 14 doses
Sifalimumab IV 10.0 mg/ 43 40.3 ± 10.9 NR 35 (81.4) 32 (74.4) NR 12.2 ± 6.4 NR NR 43 (100) NR 28 (65.4) NR
kg biweekly until 14 doses
Placebo 40 44.8 ± 10.9 NR 26 (65.0) 25 (63.0) NR 10.8 ± 5.0 NR NR 39 (97.5) 21 (52.5) NR 32 (80.0) NR
Merrill et al. [18], 2010a (3)
Rituximab IV 169 40.2 ± 11.4 NR 106 NR 8.5 ± 7.2 NR NR NR NR NR NR 67 (39.7) 14.0 ± 5.1
1000 mg days 1, 15, 168, (62.7)
and 182
Placebo 88 40.5 ± 12.8 NR 54 (61.4) NR 8.7 ± 7.6 NR NR NR NR NR NR 39 (44.3) 14.5 ± 5.6
Rovin et al. [25], 2012 (3) Lupus nephritis
(months)
Rituximab IV 72 31.8 ± 9.6 NR 79 (55) 63 (44) 32.4 ± 48.0 NR NR 449.6 ± 785.6 NR 53 (73.6) 73.6 ± 29.4 NR 15.3 ± 6.4
1000 mg days 1, 15, 168,
and 182
217
Table 1 continued
218

Study/treatment N Age (years) Previous Previous Previous SLE SELENA- SDI Anti-dsDNA ANA C 1:80 C3 B LLN C3 (mg/dL) C1 BILAG BILAG Index
(Jadad’s Score) ISS [N (%)] CE AM duration SLEDAI (IU/mL) [N (%)] [N (%)] A or B Global Score
[N (%)] [N (%)] (years) score (mean ± SD)
[N (%)]

Placebo 72 29.4 ± 9.3 NR 28.8 ± 51.6 NR NR 383.6 ± 702.6 NR 54 (75.0) 74.1 ± 27.9 NR 15.3 ± 6.2
Wallace et al. [24], 2013 (3)
Epratuzumab IV 200 mg 39 41.0 (9.8) 16 (41.0) NR 16 (41.0) NR NR NR NR NR NR NR 29 (74.4) NR
cumulative dose (100 mg
biweekly)
Epratuzumab IV 800 mg 38 38.6 (10.4) 16 (43.2) NR 16 (43.2) NR NR NR NR NR NR NR 29 (78.4) NR
cumulative dose (400 mg
biweekly)
Epratuzumab IV 2,400 mg 37 37.2 (11.4) 13 (37.1) NR 16 (45.7) NR NR NR NR NR NR NR 25 (67.6) NR
cumulative dose (600 mg
biweekly)
Epratuzumab IV 2,400 mg 37 37.2 (10.7) 18 (48.6) NR 18 (48.6) NR NR NR NR NR NR NR 27 (69.2) NR
cumulative dose
(1,200 mg biweekly)
Epratuzumab IV 3,600 mg 38 38.0 (12.2) 18 (46.2) NR 17 (43.6) NR NR NR NR NR NR NR 22 (62.9) NR
cumulative dose
(1,800 mg biweekly)
Placebo 38 41.1 (11.3) 18 (47.4) NR 18 (47.4) NR NR NR NR NR NR NR 29 (76.3) NR

AM antimalarials, ANA antinuclear antibody, anti-dsDNA anti-double-stranded DNA, BILAG British Isles Lupus Assessment Group index, CE corticosteroids, ISS immunosuppressants, IV intravenous, LLN lower limit of normal,
N number of patients, NR not reported, SC subcutaneous, SD standard deviation, SDI Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SELENA-SLEDAI Safety of Estrogens in
Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, SLE systemic lupus erythematosus, SOC standard of care therapy
H. H. L. Borba et al.
Biologic Therapies for SLE 219

Fig. 2 Efficacy of belimumab

1 mg/kg. anti-dsDNA anti-
double-stranded DNA, BILAG
British Isles Lupus Assessment
Group Index, df degrees of
freedom, IV inverse variance,
SELENA-SLEDAI Safety of
Estrogens in Lupus
Erythematosus National
Assessment version of the SLE
Disease Activity Index, SLE
systemic lupus erythematosus,
SRI SLE Responder Index
220 H. H. L. Borba et al.

Fig. 3 Efficacy of belimumab

10 mg/kg. anti-dsDNA anti-
double-stranded DNA, BILAG
British Isles Lupus Assessment
Group Index, df degrees of
freedom, IV inverse variance,
SELENA-SLEDAI Safety of
Estrogens in Lupus
Erythematosus National
Assessment version of the SLE
Disease Activity Index, SLE
systemic lupus erythematosus,
SRI SLE Responder Index
Biologic Therapies for SLE 221

Fig. 4 Safety of belimumab

1 mg/kg. df degrees of freedom,
IV inverse variance

studies included in these analyses was observed one phase III trial) demonstrated its capacity to reduce
(I2 = 0 %). anti-dsDNA antibodies, improve lupus clinical activity,
and increase mean concentrations of C3. Moreover, it is
3.5 Efficacy of Other Biologic Agents believed that abetimus may be effective in prolonging time
to renal flare, which encourages the conduct of further
The other biologic agents included abetimus sodium, clinical trials with this agent [13, 15].
atacicept, abatacept, sifalimumab, and epratuzumab. For atacicept, the included study was a phase Ib trial that
Results regarding abetimus sodium (from one phase II and did not have sufficient power to define conclusions
222
Fig. 5 Safety of belimumab
10 mg/kg. df degrees of
freedom, IV inverse variance
regarding the effect of the drug over disease activity.
However, promising results were observed in complement
levels and SELENA-SLEDAI scores, which indicate the
need for phase II/III trials with atacicept to be performed
[14].
Abatacept was evaluated in a phase IIb study, in which
primary and second endpoints were not achieved.
H. H. L. Borba et al.
Nevertheless, the obtained results suggest that abatacept
may have a clinical activity in SLE, requiring further
investigations [19].
Two phase I studies evaluated sifalimumab. The repor-
ted results indicated that this drug may promote significant
improvements in SLE. In addition, the authors highlight the
need for more studies to be conducted evaluating
Biologic Therapies for SLE 223

Fig. 6 Tolerability of belimumab 1 mg/kg. df degrees of freedom, IV inverse variance

sifalimumab efficacy in order to better understand the
clinical effects of this agent in SLE patients [20, 23].
The results of a phase IIb trial of epratuzumab proposed
that it can improve SLE disease activity, supporting further
development of this treatment [26].
3.6 Safety of Other Biologic Agents
The safety results of the biologic therapies for SLE treat-
ment were also divided according to the outcome: adverse
events, serious adverse events, infections, deaths, infusion

Fig. 7 Tolerability of belimumab 10 mg/kg. df degrees of freedom, IV inverse variance

224 H. H. L. Borba et al.

Table 2 Efficacy of rituximab 1,000 mg

Outcome Study No. of patients Effect estimatea p value

Clinical response Merrill et al. [18], 2010a 401 1.16 (0.90 to 1.49) 0.25
Rovin et al. [25], 2012
BILAG C score or better Merrill et al. [18], 2010a 401 1.15 (0.76 to 1.73) 0.52
Rovin et al. [25], 2012
Time-adjusted AUCMB of the BILAG score, week 52 Merrill et al. [18], 2010a 401 0.10 (-0.85 to 1.04) 0.84
Rovin et al. [25], 2012
Change in SF-36 PCS, week 52 Merrill et al. [18], 2010a 401 1.24 (-3.61 to 6.08) 0.62
Rovin et al. [25], 2012
AUCMB area under the curve minus baseline, BILAG British Isles Lupus Assessment Group index, PCS physical component summary
a
Effect estimate for drug vs. placebo expressed as risk ratio (95 % CI)

reactions, malignancy, withdrawals due to lack of efficacy,
and withdrawals due to adverse events. These results are
shown in Table 4.
Statistical analyses revealed the absence of significant
differences between the biologic agents and placebo
groups, indicating that these therapies may have a
good safety profile for SLE treatment. I2 values above
50 % were not observed, indicating the absence of high
heterogeneity among the studies included in these
analyses.
4 Discussion
A significant increase in the survival rate of SLE patients
has been observed since 1950, when antimalarial drugs
became the standard treatment for lupus [4]. Recently,
biologic agents have been widely investigated for the
treatment of several autoimmune diseases and have
exhibited encouraging results regarding their efficacy and
safety in clinical trials. The expectations for novel thera-
pies under investigation for the treatment of SLE include
satisfactory control of disease activity and the prevention
of damage to multiple organs without serious or severe
adverse events [4, 5].
With regard to the results presented in clinical trials, it is
relevant to conduct a statistical analysis of compiled out-
comes to generate data with a satisfactory level of evidence
that can guide the decision making of a public health
manager. In addition, a meta-analysis can be performed
without conflicts of interest and allows the evaluation of a
large population following the grouping of the populations
that were analyzed separately in each clinical trial.
Our meta-analysis corroborates the efficacy and safety
results of the individual clinical trials, showing significant
differences between the belimumab and placebo groups in
efficacy analysis and statistical similarity between the two
groups in safety analysis. Some results were presented with
a high heterogeneity, mainly due to the different types of
included studies (phase II and III in the efficacy analysis),
besides the different populations evaluated in each study.
The Wallace et al. [22] study, for instance, is a phase II
trial that has different entry criteria and different endpoints
to the other two phase III studies. Such differences may
have played a role in the high values of I2 observed in our
efficacy analysis. Another important topic corresponds to

Table 3 Safety of rituximab

Outcome Study No. of patients Effect estimatea p value
1,000 mg
Serious adverse event Merrill et al. [18], 2010a 401 0.94 (0.72–1.23) 0.67
Rovin et al. [25], 2012
Death Merrill et al. [18], 2010a 401 2.78 (0.48–16.27) 0.26
Rovin et al. [25], 2012
Infections Merrill et al. [18], 2010a 401 0.80 (0.50–1.29) 0.36
Rovin et al. [25], 2012
Infusion reactions Merrill et al. [18], 2010a 401 1.01 (0.76–1.35) 0.95
Rovin et al. [25], 2012
a Withdrawal due to adverse events Merrill et al. [18], 2010a 401 0.71 (0.38–1.34) 0.29
Effect estimate for drug vs.
placebo expressed as risk ratio Rovin et al. [25], 2012
(95 % CI)
Biologic Therapies for SLE 225

Table 4 Safety of biologic agents

Outcome Drugs No. of patients Effect estimatea p value

Adverse events Abetimus sodium [13, 15] 3,299 1.00 (0.98–1.02) 0.71
Belimumab [16, 17, 21, 22]
Abatacept [19]
Sifalimumab [23]
Rituximab [25]
Epratuzumab [24]
Serious adverse events Abetimus sodium [13] 3,550 0.98 (0.83–1.17) 0.85
Atacicept [14]
Belimumab [16, 17, 21, 22]
Abatacept [19]
Sifalimumab [23]
Epratuzumab [24]
Rituximab [18, 25]
Infections Abetimus sodium [13] 3,600 0.98 (0.92–1.05) 0.64
Atacicept [14]
Belimumab [16, 17, 21, 22]
Abatacept [19]
Sifalimumab [20, 23]
Epratuzumab [24]
Rituximab [18, 25]
Deaths Abetimus sodium [13] 1,924 0.62 (0.26–1.47) 0.28
Abatacept [19]
Sifalimumab [23]
Rituximab [18, 25]
Belimumab [21]
Infusion reactions Rituximab [18, 25] 2,473 0.93 (0.78–1.11) 0.41
Sifalimumab [23]
Epratuzumab [24]
Belimumab [17, 21]
Malignancy Belimumab [17] 1,160 1.10 (0.17–7.10) 0.92
Abatacept [19]
Sifalimumab [23]
Withdrawals due to lack of efficacy Abatacept [19] 2,540 1.24 (0.89–1.74) 0.20
Epratuzumab [24]
Belimumab [17, 21, 22]
Withdrawals due to adverse events Abetimus sodium [13, 15] 3,486 1.08 (0.82–1.43) 0.59
Belimumab [17, 21, 22]
Abatacept [19]
Sifalimumab [23]
Epratuzumab [24]
Rituximab [18, 25]
a
Effect estimate for drug vs. placebo expressed as risk ratio (95 % CI)

the values obtained at week 76, which were less good when
compared with those obtained at week 52. These results
were probably observed because only one study reported
outcomes at week 76 [17]. For this reason, these outcomes
were not evaluated separately in our meta-analysis, only
contributing to the overall efficacy result.
SRI, SELENA-SLEDAI, and BILAG are indices that
evaluate SLE activity. They are measured by question-
naires and scored based on clinical symptoms, physical
signs, and laboratory findings, observed by the physician.
These disease activity instruments are all valid, reliable,
and comparable [27–29]. Improvements in these
226
parameters indicate control of the disease, which directly
reflects the treatment efficacy.
Rising anti-dsDNA antibodies and low complement
levels are hallmarks of active lupus disease, especially with
renal involvement. Thus, efficacy outcomes such as nor-
malization of low C3 and anti-dsDNA positive to negative
are very relevant in evaluating the improvement of the
immune system in SLE patients. Following the normali-
zation of low C3, which indicates that complement con-
centrations have returned to normal, it is expected that
autoimmune B cells will undergo apoptosis. This process
allows regulation of the autoimmune response and control
of disease activity, resulting in achieving improvements for
the patient [30, 31]. Normalization of these biomarkers
suggests that belimumab may prevent or improve nephritis
in SLE patients. This result is very promising and there has
been a subsequent analysis of the phase III studies dis-
cussing this subject [32], and further trials are in progress
to address this [33]. This discussion is highly relevant as
belimumab has not been indicated for the treatment of
severe lupus nephritis or in patients with central nervous
system involvement related to SLE [6]. However, our
results indicate the potential of this novel drug to treat
nephritis due to its effects on C3 levels and anti-dsDNA
antibodies.
Belimumab, approved by the FDA in 2011 for SLE
treatment, is indicated for adults with active, autoantibody-
positive SLE, who are receiving standard therapy (anti-
malarials, prednisone, and immunosuppressive drugs). The
recommended dose of this drug is 10 mg/kg administered
by intravenous infusion over 1 hour every 2 weeks (first
three doses) and then every 4 weeks thereafter [8]. This
biologic agent is a novel medicine, and its long-term effi-
cacy and safety remain unclear. The drug has also been
approved by EMA (European Medicines Agency); how-
ever, due to economic reasons, belimumab may not be
available in the UK, where the high costs of the drug is an
important concern [34, 35]. Therefore, economic issues
would be worthy of further prospective studies.
It was possible to evaluate only four RCTs in our meta-
analysis, indicating the need for further clinical trials.
Therefore, observational studies must be conducted to
analyze a large population over a long period. These
studies should focus on the safety profile of the drug,
evaluating its long-term safety, which can contribute to the
results of clinical trials [36].
Rituximab, a chimeric monoclonal antibody that pro-
motes CD20? B cell depletion, is approved for the treat-
ment of non-Hodgkin’s lymphoma, chronic lymphocytic
leukemia, rheumatoid arthritis, microscopic polyarteritis,
and Wegener’s granulomatosis [7, 25]. Some open trials
have proposed the use of rituximab for the treatment of
SLE [37, 38]. Recently, the effects of this biologic agent
H. H. L. Borba et al.
have been investigated in RCTs, allowing a systematic
review to be performed regarding its efficacy and safety for
SLE treatment [18, 25]. Our efficacy meta-analysis showed
no significant differences between the rituximab and pla-
cebo groups, corroborating the findings of the two evalu-
ated studies. This indicates the absence of rituximab
superiority over placebo regarding the evaluated endpoints.
However, it is not possible to exclude the possibility of
positive effects in SLE patients treated with rituximab,
since several open-label studies have exhibited encourag-
ing results, especially in patients with treatment-refractory
lupus nephritis [25]. Therefore, more RCTs should be
performed and more endpoints should be evaluated. Con-
cerning its safety profile, our results suggested that ritux-
imab is a safe agent for SLE treatment.
Although satisfactory results were obtained for the
safety of biologic agents in this study, it is still necessary to
perform a meta-analysis regarding the efficacy of these
drugs. In this way, it will become possible to obtain the
best scientific evidence to guide the responsible inclusion
of these drugs for public health. To perform such a meta-
analysis, more randomized clinical trials assessing the
efficacy and safety of biologic agents must be conducted.
In the present study, it was possible to perform meta-
analyses regarding only seven biologic agents, although
our search strategy investigated 20 drugs. Data that would
have enabled us to conduct meta-analyses relating to the
other drugs included in the search strategy are not available
in the literature, as no randomized trials have been pub-
lished regarding the efficacy and safety of these immuno-
biologicals for the treatment of SLE. This absence
demonstrates that many therapeutic agents are used in an
off-label manner (use of products whose records are not
included in regulatory agencies as well as use for purposes
other than that recommended by the manufacturer) [39].
The use of drugs targeting a goal different from the indi-
cation recommended by the manufacturer is based on
clinical experience and not on scientific data generated by
clinical trials.
In the future, we expect that more clinical trials
regarding the use of biologic agents for SLE treatment will
be performed and published as the off-label use of several
drugs leads to scientific studies to collect data to support
such use. This gap in the literature once again demonstrates
the importance of evidence-based medicine, because clin-
ical experience alone does not provide sufficient data to
afford a new drug to the entire population.
5 Conclusions
Our results demonstrated that belimumab is a promising
therapy for SLE treatment, primarily based on the good
Biologic Therapies for SLE
safety profile presented despite the small number of ran-
domized clinical trials examined in our meta-analysis. We
did not demonstrate satisfactory results at week 76, most
likely due to the small number of randomized clinical trials
(only one for each outcome evaluated after 76 weeks of
treatment). However, the results for week 52 were rela-
tively good. Rituximab exhibited a good safety profile;
however, its efficacy data showed no superiority of the
drug over placebo. Furthermore, our meta-analyses dem-
onstrated that other biologic agents have a satisfactory
safety profile for SLE treatment, and the systematic review
results regarding the efficacy of these drugs showed that
they may contribute to disease improvement. However,
more clinical trials are necessary to provide a better
understanding of the efficacy of these drugs.
Acknowledgments and Disclosures No sources of external funding
were used in the preparation of this manuscript. The authors have no
conflicts of interest that are directly relevant to the content of this
article.
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