Arthritis & Rheumatism (Arthritis Care & Research)

Vol. 61, No. 9, September 15, 2009, pp 1143–1151

DOI 10.1002/art.24698
© 2009, American College of Rheumatology
ORIGINAL ARTICLE

Novel Evidence-Based Systemic Lupus

Erythematosus Responder Index
RICHARD A. FURIE,1 MICHELLE A. PETRI,2 DANIEL J. WALLACE,3 ELLEN M. GINZLER,4
JOAN T. MERRILL,5 WILLIAM STOHL,6 W. WINN CHATHAM,7 VIBEKE STRAND,8
ARTHUR WEINSTEIN,9 MARC R. CHEVRIER,10 Z. JOHN ZHONG,10 AND WILLIAM W. FREIMUTH10

Objective. To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II
SLE trial and demonstrate its potential utility in SLE clinical trials.
Methods. Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4,
10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens
in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36
health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321
serologically active SLE patients (antinuclear antibodies >1:80 and/or anti– double-stranded DNA antibodies >30 IU/ml)
at baseline was retrospectively evaluated using the SRI.
Results. SRI response is defined as 1) a >4-point reduction in SELENA–SLEDAI score, 2) no new BILAG A or no more
than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician’s global assessment by >0.3
points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week
52 compared with 29% of the placebo patients (P ⴝ 0.006). SRI responses were independent of baseline autoantibody subtype.
Conclusion. This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability
to define a robust responder index based on improvement in disease activity without worsening the overall condition or
the development of significant disease activity in new organ systems.

INTRODUCTION
Randomized controlled trials (RCTs) of patients with sys- ing because of the heterogeneity of disease manifestations
temic lupus erythematosus (SLE) are particularly challeng- (1), the waxing and waning course of the disease, the
variety of immunomodulating medications used to control
ClinicalTrials.gov identifier: NCT00071487. disease activity (2,3), and the lack of a standardized
The General Clinical Research Center at the University of
Southern California Keck School of Medicine, Los Angeles,
California is supported in part by the NIH (grant M01- fees, and/or honoraria (less than $10,000) from Human Ge-
RR00043). nome Sciences, and has served as a paid investment analyst
1
Richard A. Furie, MD: North Shore-Long Island Jewish consultant. Dr. Ginzler has received consultant fees, speak-
Health System, Lake Success, New York; 2Michelle A. Petri, ing fees, and/or honoraria (less than $10,000) from Human
MD, MPH: Johns Hopkins University, Baltimore, Maryland; Genome Sciences, and has served as a paid investment
3
Daniel J. Wallace, MD, FACP, FACR: Cedars-Sinai Medical consultant for Guidepoint Global and Gerson Lehrman
Center, University of California, Los Angeles; 4Ellen M. Gin- Group. Dr. Merrill has received consultant fees, speaking
zler, MD, MPH: State University of New York Downstate fees, and/or honoraria (less than $10,000) from Human Ge-
Medical Center, Brooklyn; 5Joan T. Merrill, MD: Oklahoma nome Sciences, and has served as a paid investment analyst
Medical Research Center, Oklahoma City; 6William Stohl, consultant. Dr. Stohl has received consultant fees, speaking
MD, PhD: University of Southern California Keck School of fees, and/or honoraria (less than $10,000) from Human Ge-
Medicine and Los Angeles County-University of Southern nome Sciences. Dr. Strand has received consultant fees (less
California Medical Center, Los Angeles; 7W. Winn Chatham, than $10,000 each) from Abbott Immunology, Alder, Aller-
MD: University of Alabama, Birmingham; 8Vibeke Strand, gan, Almirall, Amgen Corporation, AstraZeneca, Bexel, Bio-
MD: Stanford University, Palo Alto, California; 9Arthur genIdec, CanFite, Centocor, Chelsea, Crescendo, Cypress
Weinstein, MD, FACP, FACR: Washington Hospital Center, Biosciences, Inc., Euro-Diagnostica, FibroGen, Forest Labo-
Washington, DC; 10Marc R. Chevrier, MD, PhD, FACR (cur- ratories, Genentech, Human Genome Sciences, Idera, In-
rent address: Centocor, Inc., Horsham, Pennsylvania), Z. cyte, Jazz Pharmaceuticals, Lexicon Genetics, Logical Ther-
John Zhong, PhD, William W. Freimuth, MD, PhD: Human apeutics, Lux Biosciences, MedImmune, Merck Serono,
Genome Sciences, Rockville, Maryland. Novartis Pharmaceuticals, Novo Nordisk, Nuon, Ono Phar-
Dr. Furie has received consultant fees, speaking fees, maceuticals, Pfizer, Procter & Gamble, Rigel, Roche, Sanofi-
and/or honoraria (less than $10,000) from Human Genome Aventis, Savient, Schering-Plough, SKK, UCB, Wyeth, and
Sciences. Dr. Petri has received consultant fees, speaking Xdx, and serves on the advisory boards for Abbott,

1143
1144 Furie et al

method for defining response. The American College of overall changes in disease activity. It should also be able to
Rheumatology (ACR), the Food and Drug Administration simultaneously identify improvement and worsening in
(FDA), the Outcome Measures in Rheumatology Clinical the same and/or different organ systems, be validated by a
Trials (OMERACT), the European League Against Rheu- long-term RCT, and be compatible with regulatory require-
matism (EULAR), and clinical experts recommend that ments of the FDA and European Medicines Evaluation
SLE clinical trials include outcome measures assessing Agency (4,5,8).
cumulative organ damage, SLE disease activity, health- The largest phase II RCT in SLE completed to date ex-
related quality of life (HRQOL), and adverse events (3– 8). amined the efficacy of belimumab in patients with active
In 1987, members of the Systemic Lupus International SLE who were receiving standard of care therapy (SOC)
Collaborating Clinics (SLICC) initiated an effort to develop (32). Belimumab, a fully human monoclonal antibody to B
a consensus for disease activity indices (DAIs) and out- lymphocyte stimulator (BLyS; trademark of Human Ge-
come measures for RCTs of SLE. Since that time, numer- nome Sciences, Rockville, MD), was developed to selec-
ous instruments have been used in SLE clinical studies, tively inhibit the biologic activity of soluble BLyS (33).
including but not limited to the Systemic Lupus Erythem- Elevated levels of BLyS (a promoter of B cell survival, B
atosus Disease Activity Index (SLEDAI) (9), the modifica- cell differentiation, and Ig class switching) have been
tions to the SLEDAI that were developed for the Safety of shown to correlate with increased SLE disease activity
Estrogens in Lupus Erythematosus: National Assessment (32,34). In this phase II trial, exploratory analyses identi-
trial (SELENA–SLEDAI) (10), and the British Isles Lupus fied a major subpopulation of SLE patients who were se-
Assessment Group (BILAG) instrument (11,12), their rologically active, indicative of B cell hyperactivity, and
SLE flare indices (13,14), as well as the SLICC/ACR dam- more responsive to belimumab therapy than to placebo as
age index (15). determined by DAIs of SLE and HRQOL (32,35,36).
The SLEDAI, Systemic Lupus Activity Measure (SLAM), Evidence-based exploratory analyses of this RCT led to
and BILAG have performed in effective and reliable man- the creation of a robust individual responder index, which
ners in studies; furthermore, they correlate with one an- not only could be used as a primary end point in SLE trials,
other (6,16,17). The SLEDAI, SELENA–SLEDAI, SLEDAI but also could define a clinically meaningful change. The
2000 update (SLEDAI-2K) (18 –21), and BILAG (11,12,22) SLE responder index (SRI) utilizes the SELENA–SLEDAI
have been successfully used in observational trials and score to determine global improvement, BILAG domain
case studies, although baseline DAI scores were not always scores to ensure no significant worsening in heretofore
predictors of subsequent damage or other outcomes unaffected organ systems, and physician’s global assess-
(23,24). These DAIs were validated in the context of long- ment (PGA) to ensure that improvements in disease activ-
term observational studies and not in RCTs (3,6,7,9,12,22). ity are not achieved at the expense of the patient’s overall
The few RCTs conducted have shown that improvement in condition, which may have been missed by either DAI.
DAI scores correlated with response rates, disease remis-
sion, and flare prevention (3,6,25,26). However, a thresh-
old of clinically meaningful change has not been estab- PATIENTS AND METHODS
lished in studies performed with the investigational agents
anti–CD40 ligand antibody (27), dehydroepiandrosterone Study design and entry criteria. The evidence base for
(28), abetimus sodium (29), mycophenolate mofetil (30), or the SRI evaluation came from a phase II dose-ranging RCT
rituximab (31). A responder index developed in collabo- evaluating the safety, tolerability, biologic activity, and
ration with the FDA defined response as improvement efficacy of belimumab combined with SOC in 449 SLE
and/or no deterioration in patient- and physician-reported patients who had SELENA–SLEDAI scores of ⱖ4 at base-
outcomes (28). line (32). Patients with a diagnosis of SLE by ACR criteria
In 2005, the FDA released draft guidance on the devel- (37) and a history of measurable autoantibodies who were
opment of drugs for the treatment of SLE that covered the receiving a stable SOC regimen (2) for at least 60 days prior
use of DAIs, flares, and organ-specific outcomes (4). Based to day 0 (first dose) were included; patients with active
on the FDA, OMERACT, and EULAR recommendations, lupus nephritis or central nervous system disease were
the ideal responder index should detect early as well as excluded. Concurrent corticosteroid and immunosuppres-
sive agents could be changed throughout the protocol as
clinically indicated. All patients gave informed consent
Amgen, BiogenIdec, BMS, CanFite, Centocor, Chelsea, Cre- for the study, and there was an independent data safety
scendo, Cypress, Euro-Diagnostica, Fibrogen, Forest, Idera,
monitoring committee (32).
Incyte, Jazz, Nicox, Novartis, Pfizer, Rigel, Roche, Savient,
Schering-Plough, UCB, and Wyeth. Dr. Chevrier holds a
patent for the definition of systemic lupus erythematosus Patient population. A major subset of patients (n ⫽ 321)
serologic activity. Drs. Zhong and Freimuth own stock identified as serologically active (antinuclear antibodies
and/or hold stock options in Human Genome Sciences.
[ANA] ⱖ1:80 by HEp-2 cell immunofluorescence and/or
Address correspondence to Richard A. Furie, MD, Divi-
sion of Rheumatology and Allergy-Clinical Immunology, anti– double-stranded DNA [anti-dsDNA] antibodies ⱖ30
North Shore-Long Island Jewish Health System, 2800 Mar- IU/ml) at screening and baseline (day 0) were found to
cus Avenue, Suite 200, Lake Success, NY 11042. E-mail: respond better to belimumab therapy than to placebo (32).
[email protected]. Representing 71.5% of the original cohort, these patients
Submitted for publication October 21, 2008; accepted in
revised form May 7, 2009. were assessed to evaluate components of DAIs of SLE in
developing the SRI.
Belimumab in SLE 1145

Table 1. Baseline demographic and clinical characteristics of serologically active patients (n ⴝ 321)*

Belimumab

Placebo 1.0 mg/kg 4.0 mg/kg 10.0 mg/kg All active

(n ⴝ 86) (n ⴝ 78) (n ⴝ 79) (n ⴝ 78) (n ⴝ 235)

Women 93.0 96.2 94.9 97.4 96.2

Race
White 65.1 69.2 62.0 69.2 66.8
African American 24.4 23.1 31.6 26.9 27.2
Hispanic or Latino origin 19.8 15.4 25.3 19.2 20.0
Age, mean ⫾ SD years 41.3 ⫾ 11.3 39.8 ⫾ 11.5 41.0 ⫾ 10.5 40.1 ⫾ 10.9 40.3 ⫾ 10.9
Disease duration, mean ⫾ SD years 8.1 ⫾ 7.5 9.2 ⫾ 7.8 10.2 ⫾ 9.3 8.5 ⫾ 7.6 9.3 ⫾ 8.3
SELENA–SLEDAI score, mean ⫾ SEM 9.7 ⫾ 0.6 10.4 ⫾ 0.6 9.5 ⫾ 0.5 9.8 ⫾ 0.5 9.9 ⫾ 0.3
ⱖ1 A or 2 B BILAG scores 59.3 66.7 67.1 73.1 68.9
PGA, mean ⫾ SEM 1.3 ⫾ 0.05 1.6 ⫾ 0.06 1.5 ⫾ 0.05 1.5 ⫾ 0.06 1.5 ⫾ 0.03
Daily prednisone use 73.3 71.8 73.4 71.8 72.3
⬎7.5 mg at baseline 45.4 38.5 36.7 43.6 39.6
Immunosuppressive agent use† 47.7 46.2 59.5 50.0 51.9
BLyS ALOD 47.7 56.4 50.6 50.0 52.3
ANAs ⱖ1:80 94.2 97.4 97.5 92.3 95.7
Anti-dsDNA antibodies ⱖ30 IU/ml 67.4 75.6 67.1 68.0 70.2
Low C3 (⬍90 mg/dl) 30.2 47.4 38.0 42.3 42.6
Low C4 (⬍16 mg/dl) 41.9 60.3 46.8 52.6 53.2

* Values are the percentage unless otherwise indicated. SELENA–SLEDAI ⫽ Safety of Estrogens in Lupus Erythematosus: National Assessment version
of the Systemic Lupus Erythematosus Disease Activity Index; BILAG ⫽ British Isles Lupus Assessment Group; PGA ⫽ physician’s global assessment;
BLyS ⫽ B lymphocyte stimulator; ALOD ⫽ above level of detection (0.350 ng/ml); ANAs ⫽ antinuclear antibodies; anti-dsDNA ⫽ anti– double-
stranded DNA.
† Excluding aminoquinolines (hydroxychloroquine, chloroquine, and quinacrine).

SLE disease activity and efficacy measures: DAIs. The ening in PGA (⬍0.3-point increase from baseline). If all 3
SELENA–SLEDAI (10), SLE flare index (SFI) (13), PGA, criteria were met, the patient was considered a responder
BILAG (11,22), and Short Form 36 (SF-36) (38) were de- at that particular point in time; otherwise, the patient was
termined every 4 weeks during the first 24 weeks of the considered a nonresponder.
study and then at weeks 32, 40, 48, and 52. A reduction of
ⱖ4 points in the SELENA–SLEDAI score from baseline Statistical methods. An exploratory analysis limited to
was considered to be a clinically meaningful improvement patients with serologic activity at screening and baseline
(39). PGA (10,13) scores of 0, 1, 2–2.5, and 3 were bench- was performed on all disease activity scales and efficacy
marks on a 10-cm visual analog scale (VAS) corresponding parameters at the week 52 visit. Because of the general lack
to no, mild, moderate, or severe life-threatening lupus of a dose response observed in biomarkers, efficacy param-
disease activity, respectively. An increase in ⱖ1 unit from eters, or safety measures, the 3 belimumab treatment
the last assessment was considered a mild/moderate flare, groups were combined (n ⫽ 235) and compared with the
whereas an increase to ⬎2.5 points was considered a se- placebo-treated patients (n ⫽ 86) (32). The SRI and all of
vere flare (13). An increase of ⱖ0.3 points (⬎10% on the the other categorical data were analyzed using the likeli-
3-point VAS) from baseline was considered clinically sig- hood ratio chi-square test, and the percent change from
nificant worsening (40). The SFI identifies mild/moderate baseline in PGA was analyzed using a Student’s t-test. The
flares or severe flares based on clinical activity, PGA, or the absolute change from baseline in the SF-36 physical com-
need for additional treatment (13). A severe flare by the ponent summary (PCS) was analyzed using an analysis of
classic BILAG is defined as a new organ domain score of A, variance, adjusting for the baseline PCS score. For other
whereas a moderate flare is defined as a new organ domain study end points, discrete variables were analyzed using a
score of B (14). Biomarkers and laboratory parameters rou- likelihood chi-square test and continuous variables were
tinely measured with the SLE disease activity scales have analyzed using a Student’s t-test.
been described (32). Missing data in the SELENA–SLEDAI, BILAG, and PGA
were imputed using a last observation carried forward
SRI calculations. The SRI was calculated any time the method. A sensitivity analysis of the SRI was also per-
SLE disease activity scores were measured in individual formed, in which discontinuation before the week 52 visit
patients. A responder was defined as having a ⱖ4-point was considered to be a treatment failure. Analysis of the
reduction from baseline in SELENA–SLEDAI score and no selected efficacy end points was performed in a modified
new BILAG A organ domain scores or ⱖ2 new BILAG B intent-to-treat population, defined as all patients who were
organ domain scores compared with baseline and no wors- randomized and received at least 1 dose of study drug or
1146 Furie et al

as shown in Table 1. The serologically active patients,

representing 71.5% of the enrolled patient population, had
baseline demographics similar to the entire cohort (32),
except for a higher percentage with anti-dsDNA antibodies
(69.5% versus 49.7%), ANAs ⱖ1:80 (95.3% versus 71.2%),
a history of immunologic disorder per the ACR SLE crite-
ria (84.4% versus 72.6%), and low C3 (39.3% versus
30.1%) or C4 (50.2% versus 40.1%) levels.

Efficacy. Changes from baseline in SELENA–SLEDAI

scores. Three analyses compared week 52 belimumab
treatment responses with placebo in the serologically ac-
tive population (Figure 1): 1) percent change in SELENA–
SLEDAI scores, 2) percentage of patients achieving a
threshold of absolute change in SELENA–SLEDAI score by
1-point increments of improvement or worsening (range
⫺5 to ⫹5, respectively), and 3) percentage of patients
with ⱖ4-point improvement. The percent reductions in
SELENA–SLEDAI scores at week 52 were statistically
greater in the belimumab group than in the placebo group
(⫺28.8% versus ⫺14.2%; P ⫽ 0.044) (Figure 1A). There
were significantly more patients with ⬎0 to ⱕ2–point im-
provements in the belimumab group than in the placebo
group; a trend of belimumab-treated patients achieving ⱖ3
to ⱕ5–point improvements without reaching statistical
significance was also observed (Figure 1B). Compared with
placebo, significantly fewer patients treated with beli-
mumab had worsening of SELENA–SLEDAI scores at all
incremental changes of ⬎0 to ⱕ5 points. A larger percent-
age of patients had a ⱖ4-point reduction in SELENA–
SLEDAI score in the belimumab group than in the placebo
group at all time points (not significant), with separation
beginning at week 16 (Figure 1C and Table 2).
PGA and SF-36 PCS. Among the serologically active
patients, the PGA scores in the belimumab-treated patients
were significantly lower than the scores observed in the
placebo-treated patients, both early (weeks 4, 8, and 16)
and late (weeks 48 and 52) in the study. A 32.7% reduction
in PGA score at week 52 in the belimumab group was
Figure 1. The effect of belimumab on the Safety of Estrogens in observed versus a 10.7% reduction with placebo treatment
Lupus Erythematosus: National Assessment (SELENA) version of
(P ⫽ 0.001) (Figure 2A). Similarly, the PCS score of the
the Systemic Lupus Erythematosus Disease Activity Index
(SLEDAI) score at week 52 in serologically active patients (n ⫽ SF-36 improved significantly more in the belimumab
321). A, Percent change in SELENA–SLEDAI score from baseline group than in the placebo group at weeks 12, 24, 48, and 52
over time. B, Absolute changes from baseline in SELENA–SLEDAI (⫹3.0 versus ⫹1.2 points at week 52; P ⫽ 0.041) (Figure
score at week 52. C, Percentage of patients with a ⱖ4-point reduc-
2B). A 2.5-point increase is considered the minimum clin-
tion in SELENA–SLEDAI score. a ⫽ statistically significant better
response with all active belimumab vs. placebo (P ⫽ 0.04); b ⫽ ically important difference in the SF-36 PCS from baseline
statistically significant better response with all active belimumab (35,36), which was observed only in the belimumab group
vs. placebo (P ⬍ 0.05). from week 24 onward.
BILAG organ domain flares. There were no significant
placebo. The SRI analyses were retrospectively applied to differences between the belimumab and placebo groups in
the phase II data of all of the patients and the serologically the percentages of patients who developed new A or B
active subset. The analyses were not subjected to multiple organ domain scores at week 52 (29.4% versus 39.5%; P ⫽
comparison adjustment. 0.087) (34). However, focusing on specific organ domains
(Figure 3), significantly fewer belimumab-treated patients
than placebo-treated patients had new BILAG A or B flares
RESULTS in the renal (P ⫽ 0.034), neurologic (P ⫽ 0.035), and
musculoskeletal (P ⫽ 0.008) domains. A favorable trend
Demographics and baseline characteristics of serologi- was seen in the cardiorespiratory (P ⫽ 0.060) organ do-
cally active SLE patients. There were no significant dif- main. Incorporating a higher threshold for SLE flares, there
ferences across treatment groups in any of the parameters, were fewer new 1 A or ⱖ2 B organ domain flares at week
Belimumab in SLE 1147

Table 2. Summary of efficacy results for serologically active patients at week 52 (n ⴝ 321)*

Belimumab

Placebo 1.0 mg/kg 4.0 mg/kg 10.0 mg/kg All active

(n ⴝ 86) (n ⴝ 78) (n ⴝ 79) (n ⴝ 78) (n ⴝ 235) P†

SRI response rate, %‡ 29.1 48.7 43.0 46.2 46.0 0.006

ⱖ4-point reduction in SELENA– 39.5 52.6 48.1 47.4 49.4 0.117
SLEDAI score
No worsening by BILAG§ 81.4 88.5 94.9 91.0 91.5 0.015
No worsening by PGA¶ 76.7 89.7 88.6 92.3 90.2 0.003
Modified SRI, no.# 74 70 67 68 205
Baseline SELENA–SLEDAI 8.2 8.1 8.2 8.1 8.2
score, mean
Modified SRI response rate, %# 32.4 48.6 46.3 47.1 47.3 0.025

* Serologically active patients are those with antinuclear antibodies ⱖ1:80 and/or anti– double-stranded DNA (anti-dsDNA) antibodies ⱖ30 IU/ml at
screening and day 0. SRI ⫽ systemic lupus erythematosus responder index; SELENA–SLEDAI ⫽ Safety of Estrogens in Lupus Erythematosus: National
Assessment version of the Systemic Lupus Erythematosus Disease Activity Index; BILAG ⫽ British Isles Lupus Assessment Group; PGA ⫽ physician’s
global assessment.
† From likelihood ratio test for pairwise comparison between combined all active belimumab vs. placebo.
‡ Percentage of patients with a reduction in SELENA–SLEDAI score of ⱖ4, no worsening by BILAG index (no new A or 2B flares), and no worsening
by PGA (⬍0.3-point increase).
§ No new A or 2B BILAG flares.
¶ Less than 0.3-point increase in PGA from baseline.
# Modified SRI by excluding both anti-dsDNA and low complement (C3/C4) levels from the determination of the SELENA–SLEDAI score. The number
of patients with a minimum score of ⱖ4 at baseline and their mean baseline score are shown for each treatment group.

52 in the belimumab group than in the placebo group occurred in the belimumab-treated group than in the pla-
(8.5% versus 18.6%; P ⫽ 0.015) (Table 2). cebo group, with separation after week 12. Statistical sig-
SRI. In serologically active patients, the week 52 re- nificance was reached at week 52 (46% with belimumab
sponse rates for the SRI and its 3 components are shown in versus 29% with placebo; P ⫽ 0.006) (Figure 4A) and week
Table 2. No dose response was evident across the 3 beli- 56 (49% with belimumab versus 35% with placebo; P ⫽
mumab dosing groups. Higher SRI response rates over time 0.029) (data not shown). A greater percentage of patients
who received belimumab achieved a ⱖ4-point improve-
ment in SELENA–SLEDAI score at week 52 than in the
placebo group (49.4% versus 39.5%; P ⫽ 0.117). Patients
who received belimumab were more likely to have no
worsening (⬍0.3-point increase) in PGA at week 52 (90.2%
versus 76.7%; P ⫽ 0.003) and have no new A or 2 B BILAG
flares (91.5% versus 81.4%; P ⫽ 0.015) than those in the

Figure 2. The effect of belimumab on the physician’s global Figure 3. The effect of belimumab on British Isles Lupus Assess-
assessment (PGA) and Short Form 36 (SF-36) scores at week 52 in ment Group (BILAG) domain scores at week 52 (new A or B
serologically active patients (n ⫽ 321). A, Percent change in PGA. scores). The percentages of serologically active patients with new
B, Absolute point change in SF-36 physical component summary 1 A or 1 B BILAG organ domain scores at week 52 are shown. a ⫽
(PCS) scores. a ⫽ statistically significant better response with all statistically significant better response with all active belimumab
active belimumab vs. placebo (P ⬍ 0.05). vs. placebo (P ⬍ 0.05).
1148 Furie et al

tients (26%) did not meet SRI criteria because of worsen-

ing disease activity (2 PGA, 3 BILAG, and 4 PGA plus
BILAG). In comparison, of 116 belimumab-treated patients
with a ⱖ4-point improvement in SELENA–SLEDAI score
at week 52, 8 patients (7%) did not meet SRI criteria
because of worsening disease activity (2 PGA, 4 BILAG,
and 2 PGA plus BILAG). Even if dropouts before week 52
were assumed to be nonresponders at 52 weeks, a greater
percentage of serologically active patients treated with
belimumab achieved a response as defined by the SRI
(40.9% versus 27.9% with placebo; P ⫽ 0.031) (data not
shown).
An analysis of all belimumab-treated patients stratified
by autoantibody subtype (anti-dsDNA, anti-RNP, anti-Ro,
anticardiolipin, and anti-Sm; n ⫽ 63–165 per subgroup) at
baseline revealed that the week 52 SRI responses were
comparable (40 –51%) across the 5 different autoantibody
subtypes and the serologically active (46%) group (n ⫽
235) (Figure 4B). An analysis of all of the patients (n ⫽
449) irrespective of baseline autoantibody status demon-
strated a significantly higher SRI response rate at week 52
in the combined belimumab treatment group than in the
placebo group (45.9% versus 35.4%; P ⫽ 0.045) (data not
shown).

Figure 4. A, Systemic lupus erythematosus responder index over DISCUSSION

52 weeks in serologically active patients (n ⫽ 321). B, Response
rate at week 52 in belimumab-treated patients with different
The lack of a gold standard to measure SLE disease activity
autoantibody subtypes at baseline. a ⫽ statistically significant or a surrogate marker endorsed by international rheuma-
better response with all active belimumab vs. placebo (P ⫽ 0.006); tology societies or national health authorities has impeded
anti-dsDNA ⫽ anti– double-stranded DNA. the development of SLE therapies. Several DAIs such as
the SLEDAI, SELENA–SLEDAI, BILAG, SLAM, and Euro-
placebo group. More patients receiving belimumab treat- pean Consensus Lupus Activity Measure (3,7) have been
ment achieved sustained SRI responses (weeks 40 –52) validated based on the concordance of scores with ex-
than those receiving placebo (26.8% versus 17.4%; P ⫽ pert opinion, acceptable interobserver variability among
0.076) (data not shown). trained evaluators, correlation between individual pati-
Sensitivity analyses of a modified SRI were performed, ents’ scores on different indices, and correlation between
in which the minimum requirement for improvement in increases in scores and clinical decisions to increase ther-
SELENA–SLEDAI score was 5, 6, or 7 points. At a thresh- apy. Although each DAI has its unique strengths and
old of a ⱖ5-point improvement, 35.9% (n ⫽ 206) of those weaknesses, all have demonstrated sensitivity to changes
in the belimumab group achieved a response compared (7) in disease activity in cohort studies, and therefore are
with 22.5% in the placebo group (n ⫽ 71; P ⫽ 0.034). More suitable for use in clinical trials. The draft FDA guidance
stringent requirements of 6- or 7-point improvements re- document recommended analyzing the results of clinical
duced the number of evaluable patients with higher base- trials to verify “that an improvement in a disease activity
line scores, but the treatment effect remained favorable, score represents clinical benefit to the patient and to assess
although not statistically significant (P ⱕ 0.242) (data not the generalizability of the results” and “that the improve-
shown). To address the impact of laboratory values on the ment in disease activity is not accompanied by worsening
SRI, analyses were performed following removal of both in other disease manifestations” (4).
the anti-dsDNA and complement components of the A reduction from baseline in SELENA–SLEDAI score by
SELENA–SLEDAI score. SRI response rates (47.3% all ac- ⱖ4 points has been defined as clinically meaningful (39).
tive belimumab versus 32.4% placebo; P ⫽ 0.025) (Table 2) As a validated instrument requiring the unambiguous
without the serologic components remained statistically elimination or normalization of SLE signs, symptoms,
different, confirming the clinical relevance of the SRI. or laboratory abnormalities, the SELENA–SLEDAI sets a
The percentage of patients with a ⱖ4-point improve- high threshold for response. With the exception of labora-
ment in SELENA–SLEDAI score defined as nonresponders tory values, it is not easily triggered by normal variations
(not achieving 1 or both of the other response criteria, PGA in disease activity. Increased disease activity using the
or BILAG) in the SRI was ⬎3-fold greater in the placebo SLEDAI or SELENA–SLEDAI has been defined as an in-
group than in the belimumab group (10.3% versus 3.4%). crease of ⱖ3 points (10,13). The SLEDAI, SLEDAI-2K, and
Of 34 placebo-treated patients who had a ⱖ4-point im- SELENA–SLEDAI scores have been validated in observa-
provement in SELENA–SLEDAI score at week 52, 9 pa- tional studies, large RCTs (3,7,10,41), and across popula-
Belimumab in SLE 1149

tions with different ethnicities and races (16,17). In addi- organ domain scores were considered for inclusion in the
tion, recent correlations of the classic BILAG and BILAG SRI as measures of assessing improvement. However, in
2004 index (42) with the SLEDAI-2K indicated that a ⱖ3- the phase II belimumab trial, both of these BILAG mea-
point reduction in SELENA–SLEDAI score correlated with sures failed to show consistent improvement for either
a clinically meaningful change in BILAG and an associated belimumab or placebo treatment because new or recurrent
reduction in therapy, whereas a ⱖ3-point increase in the C or B scores, especially in the musculoskeletal and mu-
score was associated with disease worsening and new or cocutaneous domains, were frequently triggered through
increased therapy (43). In contrast, an ACR expert panel minor fluctuations of disease activity or laboratory values.
reviewing 15 case vignettes over 2 to 3 visits thought that Whereas BILAG scoring, which is anchored with defini-
a minimum of a 7-point reduction in the SELENA–SLEDAI tions, was more sensitive to change than the SELENA–
score was clinically meaningful (44). The variations in SLEDAI, the variability was so great using the primary
defining a clinically meaningful threshold could be due to outcome definitions that improvement or worsening were
dissimilar sample sizes or baseline disease severity. often not sustained for more than 1 to 3 months at a time.
It is vital that improvement in SLE disease activity is not This suggested that defining one new B score as the cutoff
accompanied by worsening of other disease manifesta- for flare is too sensitive if the goal is to restrict flares to
tions. The choice of the BILAG to evaluate worsening those that represent clinically meaningful changes. BILAG
provided a sensitive measure of flare, because it assesses is a comparison with the prior month and is not anchored
changes in organ-specific disease activity between points to baseline values; therefore, a patient could improve from
in time and was specifically developed with the tenet of the last visit but still be worse than they were at baseline.
intent-to-treat. It is thought that the development of either Conversely, a flare could be triggered despite the patient
1 A or ⱖ2 B organ system scores represents an increase being better than at baseline.
in disease activity sufficient to add new therapy consisting A ⬎2.5-point improvement in the SF-36 PCS (value of
of steroids and/or immunosuppressive agents (11,14,22), the minimum clinically important difference) (35,36) was
underscoring this definition as an important anchor of evaluated as an additional response criterion in the SRI.
clinically meaningful change. The flare component of the The SF-36 PCS median score was significantly improved
SELENA–SLEDAI was not included in the measure of in the group treated with belimumab compared with the
worsening because it was found to be particularly prob- placebo group. Significant differences were noted as early
lematic in situations where patients with high disease as 12 weeks, and sustained increases of ⬎2.5 points were
activity at baseline triggered a severe flare based on modest observed from weeks 24 through 52. The SF-36, a generic
increases in the SELENA–SLEDAI from scores close to 12 measure of HRQOL that has been validated in RCTs of
to a score of ⬎12. SLE, offers the ability to compare SLE with other chronic
The PGA component is included in the SRI to ensure rheumatic and nonrheumatic conditions (35,36). Incorpo-
that improvement in the SELENA–SLEDAI score was not rating the SF-36 PCS as a fourth component of the SRI
achieved at the expense of worsening of the patient’s over- reduced the overall percentage of responders but increased
all condition, which might not have been detected by the the separation between active and placebo treatment (48).
BILAG or SELENA–SLEDAI. PGA has been shown to cor- Although OMERACT (8), FDA (4), and EULAR (5) guid-
relate with SLEDAI or SELENA–SLEDAI scores (9,10) and ance recommend that HRQOL be measured in RCTs of
other DAIs (3,7,10,13,17,20,41). In a study performed by SLE, the SF-36 was not included in the SRI because it is
SLICC, SLE experts compared BILAG and SLEDAI scores not a measure of SLE disease activity. Therefore, SF-36
with a physician-generated VAS in 80 cases evaluated at data will be a major secondary end point in subsequent
baseline and at 3 and 6 months. The 2 DAIs correlated well RCTs to assess the impact of treatment from the patient’s
over time, but less so with the physician VAS, indicating perspective and to correlate responses with the SRI.
that the VAS detects factors not reflected in the DAIs (45). Treatment of serologically active SLE patients with be-
In addition, OMERACT and EULAR recommend that limumab resulted in greater SRI response rates at all time
outcome measures in clinical trials include disease activ- points, especially after week 12, in comparison with pa-
ity with global and organ system scores, as well as bio- tients treated with placebo. Differences became statisti-
markers, HRQOL, and damage scores (5,8). cally significant at weeks 52 and 56. SRI response detects
In other diseases where manifestations are heteroge- improvements in both clinical disease manifestations
neous, combined responder instruments have been used to and SLE-related laboratory abnormalities. Removal of the
assess disease activity. In fact, the accepted primary regu- 2 serologic components of the SELENA–SLEDAI score did
latory end point for most rheumatoid arthritis RCTs, the not diminish the belimumab treatment effect compared
ACR criteria for 20% improvement in disease activity, with the unmodified SRI. Interestingly, anti-Sm or anti-
includes measures of signs, symptoms, and laboratory val- RNP antibodies have been associated with poorer re-
ues. It incorporates several VAS scores that assess physi- sponses or quicker times to relapse with rituximab therapy
cian and patient global status of disease activity (46), as in SLE (49); however, in the belimumab trial, the SRI
well as patient-reported pain. Furthermore, the primary response rates were similar at 1 year, irrespective of auto-
end point for Crohn’s disease, the Crohn’s Disease Activity antibody subtype at baseline. Reductions in activated or
Index, includes measures of organ involvement, signs, plasmacytoid B cells, a ⱖ50% reduction in anti-dsDNA
symptoms, laboratory values, an assessment of patient antibodies, and/or normalization of low C4 concentrations
global status, and use of medications (47). were predictive of an SRI response in this trial (50).
The BILAG composite score or reduction of A and/or B Serologically active SLE patients who achieved a ⱖ4-
1150 Furie et al

point reduction in SELENA–SLEDAI score receiving beli- P. Outcome measures to be used in clinical trials in systemic
mumab treatment for 1 year compared with those re- lupus erythematosus. J Rheumatol 1999;26:490 –7.
8. Smolen JS, Strand V, Cardiel M, Edworthy S, Furst D, Glad-
ceiving placebo were 2- to 3-fold less likely to develop
man D, et al. Randomized clinical trials and longitudinal
increased SLE disease activity as defined by BILAG (new observational studies in systemic lupus erythematosus: con-
BILAG A score or ⱖ2 B scores) or PGA (ⱖ0.3-point wors- sensus on a preliminary core set of outcome domains. J Rheu-
ening). These results suggest that belimumab has the abil- matol 1999;26:504 –7.
ity to improve and stabilize disease activity, as well as 9. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH,
and the Committee on Prognosis Studies in SLE. Derivation of
reduce flare rates in this population. In serologically active the SLEDAI: a disease activity index for lupus patients. Ar-
patients, there was a significant reduction in the time to thritis Rheum 1992;35:630 – 40.
new flares between weeks 24 and 52 as defined by the SFI 10. Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sam-
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and musculoskeletal BILAG flares at week 52 suggest that 11. Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P,
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ease manifestations than on others. instrument for measuring clinical disease activity in systemic
Retrospective application of the SRI to data from a large lupus erythematosus. Q J Med 1993;86:447–58.
12. Stoll T, Stucki G, Malik J, Pyke S, Isenberg DA. Further
phase II RCT of belimumab in patients with active SLE
validation of the BILAG disease activity index in patients
demonstrated that belimumab treatment resulted in a sta- with systemic lupus erythematosus. Ann Rheum Dis 1996;55:
tistically larger percentage of responders than treatment 756 – 60.
with placebo. This SRI, based on a responder analysis of a 13. Petri M, Buyon J, Kim M. Classification and definition of
large phase II study, has been accepted as the 52-week major flares in SLE clinical trials. Lupus 1999;8:685–91.
14. Gordon C, Sutcliffe N, Skan J, Stoll T, Isenberg DA. Definition
primary efficacy end point for 2 ongoing global phase III and treatment of lupus flares measured by the BILAG index.
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SLE patients receiving SOC with baseline SELENA– 15. Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Uro-
SLEDAI scores of ⱖ6 points, and will compare treatment witz M, et al. The development and initial validation of the
with belimumab (1 or 10 mg/kg) with placebo (Clinical- Systemic Lupus International Collaborating Clinics/Ameri-
can College of Rheumatology damage index for systemic lu-
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16. Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Bom-
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AUTHOR CONTRIBUTIONS ability of 3 disease activity indices in systemic lupus ery-
thematosus. J Rheumatol 1992;19:608 –11.
All authors were involved in drafting the article or revising it 17. Ward MM, Marx AS, Barry NN. Comparison of the validity
critically for important intellectual content, and all authors ap- and sensitivity to change of 5 activity indices in systemic
proved the final version to be published. Dr. Furie had full access lupus erythematosus. J Rheumatol 2000;27:664 –70.
to all of the data in the study and takes responsibility for the 18. Cook RJ, Gladman DD, Pericak D, Urowitz MB. Prediction of
integrity of the data and the accuracy of the data analysis. short term mortality in systemic lupus erythematosus with
Study conception and design. Furie, Petri, Wallace, Chatham, term dependent measures of disease activity. J Rheumatol
Weinstein, Chevrier, Zhong, Freimuth. 2000;27:1892–5.
Acquisition of data. Furie, Petri, Wallace, Ginzler, Merrill, Stohl, 19. Danowski A, Magder L, Petri M. Flares in lupus: Outcome
Chatham, Chevrier, Zhong, Freimuth. Assessment Trial (FLOAT), a comparison between oral meth-
Analysis and interpretation of data. Furie, Petri, Wallace, ylprednisolone and intramuscular triamcinolone. J Rheuma-
Ginzler, Stohl, Strand, Weinstein, Chevrier, Zhong, Freimuth. tol 2006;33:57– 60.
20. Ibanez D, Gladman D, Urowitz M. Summarizing disease fea-
tures over time. II. Variability measures of SLEDAI-2K.
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