ARTHRITIS & RHEUMATISM
Vol. 64, No. 10, October 2012, pp 3364–3373
Long-Term Safety Profile of Belimumab Plus Standard Therapy
in Patients With Systemic Lupus Erythematosus
Joan T. Merrill,1 Ellen M. Ginzler,2 Daniel J. Wallace,3 James D. McKay,4 Jeffrey R. Lisse,5
Cynthia Aranow,6 Frank R. Wellborne,7 Michael Burnette,8 John Condemi,9
Z. John Zhong,10 Lilia Pineda,10 Jerry Klein,10 and William W. Freimuth,10
on behalf of the LBSL02/99 Study Group
Objective. To evaluate the safety profile of long-
term belimumab therapy combined with standard ther-
ClinicalTrials.gov identifiers: NCT00071487 and NCT00583362.
Supported by Human Genome Sciences, Inc. (Rockville, MD)
and GlaxoSmithKline (Uxbridge, UK).
1
Joan T. Merrill, MD: Oklahoma Medical Research Founda-
tion, Oklahoma City; 2Ellen M. Ginzler, MD: State Univer-
sity of New York Downstate Medical Center, Brooklyn; 3Daniel J.
Wallace, MD, PhD: Cedars-Sinai Medical Center and David Geffen
School of Medicine, University of California, Los Angeles; 4James D.
McKay, DO: Oklahoma Center for Arthritis Therapy and Research,
Tulsa; 5Jeffrey R. Lisse, MD: Arizona Arthritis Center, University
of Arizona, Tucson; 6Cynthia Aranow, MD: Feinstein Institute for
Medical Research, North Shore–LIJ Health System, Manhasset,
New York; 7Frank R. Wellborne, DO: Houston Institute for Clinical
Research, Houston, Texas; 8Michael Burnette, MD: Tampa Medical
Group, Tampa, Florida; 9John Condemi, MD: University of Rochester
School of Medicine and Dentistry, Rochester, New York; 10Z. John
Zhong, PhD, Lilia Pineda, MD, Jerry Klein, PhD, William W.
Freimuth, MD, PhD: Human Genome Sciences, Inc., Rockville,
Maryland.
Drs. Merrill and Wallace have received consulting fees,
speaking fees, and/or honoraria from GlaxoSmithKline and Human
Genome Sciences, Inc. (less than $10,000 each). Dr. Ginzler has
received consulting fees, speaking fees, and/or honoraria from Human
Genome Sciences, Inc. (less than $10,000) and consulting fees from
investment analysts Gerson Lehrman Group and Guidepoint Global
(less than $10,000 each). Dr. McKay has received consulting fees,
speaking fees, and/or honoraria from Human Genome Sciences, Inc.
(less than $10,000) and owns stock or stock options in the company.
Dr. Aranow has received consulting fees, speaking fees, and/or hono-
raria from GlaxoSmithKline (less than $10,000). Dr. Wellborne has
received consulting fees, speaking fees, and/or honoraria from Glaxo-
SmithKline and Human Genome Sciences, Inc. (less than $10,000
each) and has received research grants from GlaxoSmithKline and
Human Genome Sciences, Inc. for belimumab clinical trials. Drs.
Zhong, Pineda, Klein, and Freimuth own stock or stock options in
Human Genome Sciences, Inc.
Address correspondence to Joan T. Merrill, MD, Clinical
Pharmacology Research Program, MS 22, Oklahoma Medical Re-
search Foundation, 825 Northeast 13th Street, Oklahoma City, OK
73104. E-mail: joan-merrill@omrf.org.
Submitted for publication December 20, 2011; accepted in
revised form May 24, 2012.
3364
DOI 10.1002/art.34564
© 2012, American College of Rheumatology
apy for systemic lupus erythematosus (SLE) in patients
with active disease.
Methods. Patients who were randomized to re-
ceive intravenous placebo or belimumab 1, 4, or 10 mg/
kg, plus standard therapy, and completed the initial
52-week double-blind treatment period were then al-
lowed to enter a 24-week open-label extension phase.
During the extension period, patients in the belimumab
group either received the same dose or were switched to
10 mg/kg and patients in the placebo group were
switched to belimumab 10 mg/kg. Patients who achieved
a satisfactory response during the 24-week extension
period were allowed to participate in the long-term
continuation study of monthly belimumab 10 mg/kg.
Adverse events (AEs) and abnormal laboratory results
were analyzed per 100 patient-years in 1-year intervals.
Results. Of the 364 patients who completed the
52-week double-blind treatment period, 345 entered the
24-week extension, and 296 continued treatment with
belimumab in the long-term continuation study. Safety
data through 4 years of belimumab exposure (1,165
cumulative patient-years) are reported. Incidence rates
of AEs, severe/serious AEs, infusion reactions, infec-
tions, malignancies, grades 3/4 laboratory abnormali-
ties, and discontinuations due to AEs were stable or
declined during 4-year belimumab exposure. The most
common AEs included arthralgia, upper respiratory
tract infection, headache, fatigue, and nausea. Serious
infusion reactions were rare: only 1 occurred during the
4-year followup period. Rates of serious infection de-
creased from 5.9/100 patient-years to 3.4/100 patient-
years, and no specific type of infection predominated.
Conclusion. Belimumab added to standard ther-
apy was generally well-tolerated over the 4-year treat-
ment period in patients with SLE, which suggests that
LONG-TERM SAFETY PROFILE OF BELIMUMAB
belimumab can be administered long term with an
acceptable safety profile.
Systemic lupus erythematosus (SLE) is a chronic
multisystem autoimmune disorder with a variable and
unpredictable clinical course, which is characterized by
autoantibody formation and fluctuating inflammation
(1,2). Current standard therapy for the management of
SLE involves the use of corticosteroids, antimalarial
agents, and immunosuppressive agents, either alone or
in combination (3–6). Current treatments are widely
acknowledged to have potentially dangerous side effects,
especially when used in the long term.
Despite improvements in the treatment and
prognosis of SLE during the past several decades, these
patients are at high risk of serious morbidity, including
infections (especially of the respiratory and urinary
systems), coronary artery disease, and hematologic and
solid tumors (7–14). Patients with SLE also have a
2–5-fold greater risk of death from all causes than the
general population (15,16). Thus, there are significant
unmet needs in this population.
Biologic agents targeting specific immunologic
pathways offer a new approach to the treatment of SLE.
B lymphocyte stimulator is a critical cytokine for the
maturation and survival of B cells (17). This cytokine is
overexpressed in patients with SLE and other auto-
immune diseases, and the levels correlate with increased
SLE disease activity and elevated titers of anti–double-
stranded DNA antibody (18–22). Belimumab (Benlysta;
Human Genome Sciences, Inc. and GlaxoSmithKline) is
a human IgG1␭ monoclonal antibody that binds to
soluble human B lymphocyte stimulator and inhibits its
biologic activity (18,19).
The results of a phase II, placebo-controlled,
dose-ranging trial of belimumab in 449 patients with
active SLE who were receiving standard therapies for
the disease have previously been reported (23). Beli-
mumab was generally well tolerated, and the incidence
rates of adverse events (AEs) and abnormal laboratory
findings were similar across the active treatment and
placebo groups. The coprimary efficacy end points in
that study, however, were not met. A post hoc analysis
identified a subset of patients (72% of the original co-
hort) with autoantibody-positive SLE (antinuclear anti-
body titer ⱖ1:80 or anti–double-stranded DNA ⱖ30 IU/
ml) in whom belimumab reduced the disease activity and
risk of SLE flare as compared with placebo. In 2 pivotal
phase III studies, autoantibody-positive patients with
SLE who were receiving standard therapy were random-
3365
ized to placebo or belimumab 1 or 10 mg/kg and treated
for 48 or 72 weeks (24,25). Both trials met the primary
end point, demonstrating a significantly higher response
rate (as assessed by the SLE Responder Index) at week
52 in patients treated with belimumab. In addition,
belimumab was generally well tolerated in these studies,
with an overall safety profile similar to placebo.
The present study is an ongoing open-label con-
tinuation study of the original phase II trial, which was
designed to assess the safety profile of belimumab over
4 years of exposure in combination with standard ther-
apy in patients with active SLE (23).
PATIENTS AND METHODS
Study design. The initial study enrolled patients with
active SLE in a 52-week phase II randomized, double-blind,
placebo-controlled trial of intravenous belimumab (1, 4, or
10 mg/kg; administered on days 0, 14, and 28 and then every 28
days thereafter) plus standard therapy, which could include
corticosteroids, antimalarial agents, and immunosuppressants,
either alone or in combination (23). Patients completing the
52-week double-blind period entered a 24-week open-label
extension phase. During this phase, belimumab patients either
received the same dose or were switched to 10 mg/kg at the
investigator’s discretion, and placebo patients were switched to
belimumab 10 mg/kg. Upon completion of the 24-week exten-
sion period, patients who had achieved a satisfactory response
to therapy (defined as an improvement in the physician’s
global assessment score versus baseline [day 0] or versus week
52 and no severe SLE flare in the last 30 days of the extension
period) could enter a long-term open-label continuation pro-
tocol and receive intravenous belimumab 10 mg/kg every 28
days. Standard therapy (i.e., background medications) could be
altered anytime during the course of a patient’s participation in
any of these studies according to the opinion of the treating
physician. The addition of intravenous cyclophosphamide or
new biologic agents, however, was not permitted. The primary
objective of the extension and continuation studies was to
evaluate the long-term safety and tolerability of belimumab in
these patients.
The studies were reviewed and approved by an in-
stitutional review board or ethics committee at each study
site, and all patients gave informed consent before continuing
in the long-term protocol. The initial and long-term trials
are registered as ClinicalTrials.gov nos. NCT00071487 and
NCT00583362, respectively.
Safety data monitoring during the phase II and 24-
week extension studies was performed by an independent
external data monitoring committee that met approximately
every 3 months. During the long-term continuation period, a
sponsor committee reviewed the safety data approximately
every 6 months.
Safety measures. Adverse events were recorded ap-
proximately every 4 weeks during both studies. Laboratory
data for safety assessments (hematology, chemistry, coagula-
tion, Ig isotypes [IgG, IgA, IgM, and IgE], and urinalysis) were
3366 MERRILL ET AL

collected every 2 months throughout the studies. AEs were reasons for discontinuation were patient request (6%)
coded using the Medical Dictionary for Regulatory Activities and AE (5%), and the rates declined over time.
(MedDRA) version 13.1 and were graded for severity using the Summary of adverse events. The incidence rates
Adverse Event Severity Grading Tables, modified from the
of AEs, treatment-related AEs, and serious and/or se-
Adult Toxicity Tables of the Division of Microbiology and
Infectious Diseases, National Institute of Allergy and Infec- vere AEs were similar, as previously reported, for the
tious Diseases (26). placebo and belimumab groups during the double-blind
Statistical methods. The pooled results at all beli- portion of the study, and these rates either remained
mumab doses were compared with placebo during the 52-week stable or declined over the 4 years of belimumab expo-
double-blind period (23). For the long-term continuation sure (23) (Figure 2). The most common MedDRA
analysis, data were pooled and presented by 1-year intervals system organ class AEs reported throughout the 4-year
starting from the time patients received their first dose of
period was infections and infestations, with upper respi-
belimumab plus 28 days. Data were pooled because no dose
response was observed in the safety measures and since after ratory tract infections predominating (Table 2). The
1.5 years in the study, all patients continued with belimumab most common AEs included arthralgia, upper respira-
10 mg/kg. The data set used for analysis included 4 years of tory tract infection, headache, fatigue, and nausea. The
belimumab exposure for patients originally randomized to serious AEs of highest incidence (5 patients in any year)
receive belimumab and for patients who switched to beli- were cellulitis and transient ischemic attack, both with
mumab after 1 year of placebo treatment. Data from patients incidence rates of 1.3/100 patient-years in year 1 and
who received placebo during the double-blind period who
with declining rates over time.
switched to belimumab were combined with data from all
patients who were originally receiving belimumab, i.e., the first
year of belimumab treatment was the second year in the study Table 1. Baseline demographic and clinical characteristics of the
for patients originally assigned to placebo. 296 SLE patients participating in the long-term continuation period*
Incidence rates of AEs and abnormal laboratory find-
ings are expressed per 100 patient-years for each 1-year Women, no. (%) 276 (93.2)
interval. For patients who discontinued during a given interval, Race/ethnicity, no. (%)
Caucasian 213 (72.0)
8 weeks of followup safety data were included in the last Black/African American 65 (22.0)
interval, if available. Asian 5 (1.7)
Adverse events of special interest, i.e., infusion-related Other 13 (4.4)
reactions (including hypersensitivity reactions), infections, Age, mean ⫾ SD years 42.6 ⫾ 11.5
and malignant neoplasms, were evaluated by creating com- Disease duration, mean ⫾ SD years 8.8 ⫾ 7.8
posite definitions of these events using MedDRA preferred Disease activity
SELENA–SLEDAI score, mean ⫾ SD 9.2 ⫾ 4.55
terms.
No. (%) with ⱖ1 BILAG A or ⱖ2 BILAG B 190 (64.2)
domain scores
Physician’s global assessment score, mean ⫾ SD 1.4 ⫾ 0.51
RESULTS No. (%) with ⱖ1 severe SLE flare 40 (13.5)
Laboratory assessments, no. (%)
Patient disposition and baseline demographics. ANA titer ⱖ1:80 (n ⫽ 294) 217 (73.8)
Baseline demographic and SLE disease characteristics Anti-dsDNA titer ⱖ30 IU/ml 149 (50.3)
of the patients who entered the long-term continuation C4 ⬍90 mg/dl (LLN) (n ⫽ 293) 122 (41.6)
C3 ⬍16 mg/dl (LLN) (n ⫽ 294) 83 (28.2)
study were similar to those of the original double-blind Grades 3/4 hypogammaglobulinemia 1 (0.3)
study population (23) (Table 1). Medication use, no. (%)
Corticosteroid use 199 (67.2)
Among the 364 patients completing the 52-week ⬎7.5 mg/day 97 (32.8)
double-blind treatment period, 345 entered the 24-week Baseline dosage, mean ⫾ SD mg/day 9.9 ⫾ 8.7
extension phase. Of the 321 patients completing the Antimalarial agents 209 (70.6)
Immunosuppressive agents 148 (50.0)
24-week extension period, 296 continued treatment Azathioprine 56 (18.9)
with belimumab 10 mg/kg monthly in the long-term Mycophenolate mofetil 42 (14.2)
continuation study (Figure 1). The cumulative patient Methotrexate 49 (16.6)
Leflunomide 12 (4.1)
exposure to belimumab after the first 4 years of treat-
ment was 1,165 patient-years from October 2003 through * Baseline information was collected at the time the systemic lupus
erythematosus (SLE) patients entered the double-blind period of the
August 2009. study. Patients were receiving 10 mg/kg of belimumab. SELENA–
The overall rate of discontinuation during the SLEDAI ⫽ Safety of Estrogens in Lupus Erythematosus National
first year of belimumab exposure was 16% and the rate Assessment version of the Systemic Lupus Erythematosus Disease
Activity Index; BILAG ⫽ British Isles Lupus Assessment Group;
decreased during years 2–4 of the long-term continua- ANA ⫽ antinuclear antibody; anti-dsDNA ⫽ anti–double-stranded
tion study (range 9–14%). In year 1, the 2 most common DNA; LLN ⫽ lower limit of normal.
LONG-TERM SAFETY PROFILE OF BELIMUMAB 3367

Figure 1. Distribution of the study patients during the open-label long-term exposure study of belimumab treatment in patients with systemic lupus
erythematosus. DC ⫽ discontinuation; DB ⫽ double-blind; pat req ⫽ patient request; AE ⫽ adverse event; dis prog ⫽ disease progression; compl ⫽
compliance; LTE ⫽ long-term extension; LTFU ⫽ lost to followup; inv dec ⫽ investigator decision.

Figure 2. Incidence rates of adverse events (AEs), infections, malignant neoplasms, and mortality over 4 years of exposure of systemic lupus
erythematosus patients to treatment with belimumab. Rate ⫽ (100 ⫻ the number of patients developing the given AE in the given interval)/(total
patient-years in the given interval). Patients orginally randomized to receive placebo were included from the time of their first belimumab exposure.
3368 MERRILL ET AL

Table 2. Summary of adverse events occurring during the double-blind period versus the long-term continuation period*
52-week double-blind
placebo-controlled period Long-term continuation period (years 1–4),
(year 1) all belimumab-treated patients

Placebo Belimumab Year 1 Year 2 Year 3 Year 4

(n ⫽ 113) (n ⫽ 336) (n ⫽ 424) (n ⫽ 339) (n ⫽ 274) (n ⫽ 248)

Total no. of patient-years 109.9 320.1 374.0 299.1 258.1 234.2

AEs/100 patient-years
AEs 110 (100.1) 326 (101.8) 413 (110.4) 322 (107.7) 260 (100.8) 237 (101.2)
Serious AEs 22 (20.0) 55 (17.2) 70 (18.7) 52 (17.4) 49 (19.0) 31 (13.2)
Severe AEs 21 (19.1) 63 (19.7) 81 (21.7) 43 (14.4) 38 (14.7) 23 (9.8)
Serious and/or severe AEs 31 (28.2) 86 (26.9) 112 (29.9) 70 (23.4) 55 (21.3) 40 (17.1)
Discontinuations due to AEs 8 (7.3) 21 (6.6) 24 (6.4) 8 (2.7) 5 (1.9) 8 (3.4)
Incidence rates of AEs by system organ class
(ⱖ50/100 patient-years in double-blind study)†
Infections/infestations 82 (74.6) 254 (79.4) 313 (83.7) 237 (79.3) 192 (74.4) 181 (77.3)
Musculoskeletal/connective tissue disorders 79 (71.9) 222 (69.4) 273 (73.0) 209 (69.9) 150 (58.1) 133 (56.8)
Skin/subcutaneous tissue disorders 57 (51.9) 193 (60.3) 219 (58.5) 133 (44.5) 83 (32.2) 69 (29.5)
Gastrointestinal disorders 63 (57.3) 187 (58.4) 223 (59.6) 149 (49.8) 102 (39.5) 74 (31.6)
Nervous system disorders 53 (48.2) 168 (52.5) 187 (50.0) 124 (41.5) 84 (32.6) 72 (30.7)
General disorders/administration site conditions 63 (57.3) 165 (51.6) 191 (51.1) 128 (42.8) 74 (28.7) 58 (24.8)
Top 6 most frequently observed AEs not of special
interest, by MedDRA preferred term‡
Arthralgia 40 (36.4) 111 (34.7) 128 (34.2) 97 (32.4) 63 (24.4) 53 (22.6)
Headache 26 (23.7) 94 (29.4) 103 (27.5) 52 (17.4) 32 (12.4) 28 (12.0)
Fatigue 34 (30.9) 87 (27.2) 94 (25.1) 56 (18.7) 22 (8.5) 17 (7.3)
Nausea 27 (24.6) 86 (26.9) 95 (25.4) 46 (15.4) 29 (11.2) 22 (9.4)
Diarrhea 19 (17.3) 61 (19.1) 67 (17.9) 32 (10.7) 29 (11.2) 11 (4.7)
Arthritis 19 (17.3) 57 (17.8) 65 (17.4) 34 (11.4) 11 (4.3) 14 (6.0)
Infusion reactions, including hypersensitivity§
Overall 23 (20.9) 79 (24.7) 87 (23.3) 32 (10.7) 14 (5.4) 14 (6.0)
Serious and/or severe 1 (0.9) 1 (0.3) 0 1 (0.3) 1 (0.4) 0
Resulted in discontinuation 1 (0.9) 1 (0.3) 1 (0.3) 0 1 (0.4) 0
Infections
Serious and/or severe 5 (4.5) 23 (7.2) 31 (8.3) 18 (6.0) 10 (3.9) 11 (4.7)
Resulted in discontinuation 1 (0.9) 3 (0.9) 3 (0.8) 0 0 1 (0.4)
Most frequent infection AEs, by MedDRA preferred term
(ⱖ10/100 patient-years in double-blind study)
Upper respiratory tract infection 33 (30.0) 101 (31.6) 118 (31.6) 78 (26.1) 65 (25.2) 67 (28.6)
Urinary tract infection 18 (16.4) 55 (17.2) 62 (16.6) 44 (14.7) 37 (14.3) 26 (11.1)
Sinusitis 21 (19.1) 43 (13.4) 52 (13.9) 48 (16.1) 56 (21.7) 28 (12.0)
Bronchitis 8 (7.3) 32 (10.0) 37 (9.9) 29 (9.7) 35 (13.6) 25 (10.7)
Infection AEs by baseline immunosuppressant use
No immunosuppressants, no. 58 167 211 164 135 119
Patient-years, no. 56.1 154.8 183.1 146.3 125.8 112.0
Overall infections 40 (71.3) 130 (84.0) 159 (86.8) 113 (77.2) 95 (75.5) 80 (71.4)
Serious and/or severe 2 (3.6) 11 (7.1) 13 (7.1) 8 (5.5) 3 (2.4) 3 (2.7)
Immunosuppressants including MMF, no. 55 169 213 175 139 129
Patient-years, no. 53.9 165.3 190.9 152.8 132.3 122.2
Overall infections 42 (78.0) 124 (75.0) 154 (80.7) 124 (81.2) 97 (73.3) 101 (82.7)
Serious and/or severe 3 (5.6) 12 (7.3) 18 (9.4) 10 (6.5) 7 (5.3) 8 (6.5)
Non-MMF immunosuppressants, no. 37 117 147 129 100 92
Patient-years, no. 37.7 118.4 137.5 110.2 94.5 86.6
Overall infections 26 (68.9) 85 (71.8) 104 (75.6) 91 (82.6) 69 (73.0) 69 (79.7)
Serious and/or severe 1 (2.7) 5 (4.2) 11 (8.0) 7 (6.4) 2 (2.1) 7 (8.1)
MMF, no. 18 52 66 46 39 37
Patient-years, no. 16.2 47.0 53.4 42.6 37.8 35.6
Overall infections 16 (99.1) 39 (83.0) 50 (93.7) 33 (77.5) 28 (74.2) 32 (90.0)
Serious and/or severe 2 (12.4) 7 (14.9) 7 (13.1) 3 (7.0) 5 (13.2) 1 (2.8)
Infection AEs by baseline corticosteroid use
No corticosteroids, no. 31 112 141 117 99 92
Patient-years, no. 29.1 107.5 126.9 105.8 94.0 89.0
Overall infections 21 (72.2) 87 (80.9) 106 (83.5) 82 (77.5) 70 (74.4) 70 (78.7)
Serious and/or severe – 3 (2.8) 4 (3.2) 3 (2.8) 2 (2.1) 4 (4.5)
Corticosteroids, no. 82 224 283 222 175 156
Patient-years, no. 80.8 212.5 247.1 193.3 164.0 145.3
Overall infections 61 (75.5) 167 (78.6) 207 (83.8) 155 (80.2) 122 (74.4) 111 (76.4)
Serious and/or severe 5 (6.2) 20 (9.4) 27 (10.9) 15 (7.8) 8 (4.9) (4.8)

* Except where indicated otherwise, values are the number of adverse events (AEs) (rate/100 patient-years). MMF ⫽ mycophenolate mofetil.
† By descending frequency of system organ class during the double-blind study period in the belimumab treatment group.
‡ By descending frequency of Medical Dictionary for Regulatory Activities (MedDRA) preferred term during the double-blind study period in the
belimumab treatment group.
§ Infusion reactions included ⬎160 MedDRA preferred terms (e.g., erythema, flushing, rash, urticaria) occurring on the day of an infusion and
having a duration of ⱕ7 days. Hypersensitivity reactions were those that started on the day of an infusion (regardless of duration) and were defined
according to the following MedDRA preferred terms: anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock,
angioedema, drug hypersensitivity, hypersensitivity, and tachyphylaxis.
LONG-TERM SAFETY PROFILE OF BELIMUMAB
Deaths. Five deaths occurred during the 4 years
of belimumab exposure, with an incidence rate of 0.4/
100 patient-years (95% confidence interval [95% CI]
0.14–1.0). Two deaths occurred during the double-blind
period: 1 suicide in a patient with history of depression
who was receiving belimumab 1 mg/kg, and 1 death
from aspiration pneumonia that led to sepsis and respi-
ratory failure in a patient who was receiving belimumab
10 mg/kg. Three deaths occurred during the long-term
continuation period: 1 death from advanced atheroscle-
rotic coronary artery disease in a patient with a history
of hypertension (during year 2), 1 suicide due to oxy-
codone and alcohol intoxication (during year 3), and 1
death from cytomegaloviral (CMV) pneumonia (during
year 4). Only the case of CMV pneumonia was consid-
ered by the investigator to be possibly related to the
study agent. That patient died of respiratory failure that
was considered to be secondary to pneumonia and
immunosuppression. The patient had history of pneu-
monia and, in addition to the belimumab, was taking
several concomitant immunosuppressants, including
corticosteroids, methotrexate, and leflunomide.
Adverse events of special interest. Infusion reac-
tions. Rates of infusion reactions, including hypersensi-
tivity reactions, were similar with placebo and beli-
mumab during the double-blind period (20.9 and 24.7/
100 patient-years, respectively). During the long-term
continuation period, the rate decreased to 6.0/100 patient-
years by year 4, with nausea and headache reported most
frequently (Table 2). Two severe and/or serious infusion
reactions were reported: a patient in year 2 with vertigo,
and a patient in year 3 with symptoms of dyspnea,
nausea, vomiting, mouth swelling, chest tightness, ab-
dominal pain, and difficulty breathing, which resolved
on the day of occurrence, but resulted in discontinuation
of belimumab. Hypersensitivity reactions were only ob-
served during the first year of belimumab exposure, were
infrequent, and included 3 patients with angioedema
(2 discontinued [1 receiving placebo and 1 receiving
belimumab] during the double-blind period) and 1 with
hypersensitivity from environmental allergies.
Infections. Infection rates remained stable during
the long-term continuation period (Table 2). Upper
respiratory tract and urinary tract infections, sinusitis,
and bronchitis were the most frequent infections in
year 1. Rates were comparable to those that had been
seen with placebo during the double-blind period. The
rate of serious and/or severe infections was highest in
year 1 (8.3/100 patient-years) and declined in years 2–4.
Individual serious infections occurred at a rate ⱕ2/
100 patient-years in any yearly interval, and no specific
infection predominated. Cellulitis and pneumonia were
3369
the most common serious infections in year 1 (1.3 and
0.8/100 patient-years, respectively), and the rates de-
clined in years 2–4. In all, 4 infections resulted in
discontinuation of belimumab in the 4-year analysis.
Opportunistic infections. Two opportunistic in-
fections were reported; both occurred during the long-
term continuation period. One opportunistic infection
reported during year 4 was assessed as not serious
(coccidioidomycosis in an endemic area of Arizona) and
was considered to be probably not related to study drug,
and the patient continued to receive belimumab treat-
ment. The other opportunistic infection (fatal CMV
pneumonia) also occurred during year 4 (described
above).
Immunosuppressant use and infection rates. The
proportions of patients taking ⱖ1 immunosuppressant
over the 4 yearly intervals during the study were fairly
constant (49–54%) (Figure 3). Incidence rates for over-
all and serious and/or severe infections during the
double-blind period were similar or numerically higher
for patients receiving belimumab as compared with
placebo, regardless of the use of immunosuppressants at
baseline (Table 2). Compared with year 1 of exposure,
the rates of overall and serious and/or severe infections
were stable or decreased during the following 3 years of
belimumab treatment regardless of the use of immuno-
suppressants at baseline.
During the double-blind period, patients who
were taking mycophenolate mofetil (MMF) at baseline
had a higher incidence of overall and serious and/or
severe infections than other patients, regardless of
whether they received placebo or belimumab (Table 2).
During the 4-year exposure period, serious and/or severe
infection rates ranged from 2.1 to 8.1/100 patient-years
in patients who did not receive MMF and from 2.8 to
13.2/100 patient-years in those who did receive MMF.
The cumulative rate of serious and/or severe infections
in patients who received MMF with belimumab over
4 years was 1.5-fold greater than that in patients who
received immunosuppressants other than MMF with
belimumab (9.4 versus 6.3/100 patient-years). Patients
who took MMF and those who did not had similar levels
of IgG, IgA, and IgM over time (data not shown).
Corticosteroid use and infection rates. Sixty-seven
percent of patients receiving belimumab were taking
corticosteroids at baseline, with an average dosage of
9.9 mg/day (Table 1). The proportion of patients taking
corticosteroids over the 4 yearly intervals during the
study decreased 9% from years 1 to 4, and the average
corticosteroid dose was reduced after the first year of
therapy (Figure 3). In these patients, the average median
percentage change from baseline for the last 30 days of
3370
Figure 3. Percentages of systemic lupus erythematosus patients receiving an immunosuppressant or corticosteroid over the 4 years of study.
a 1-year interval were 0%, ⫺25%, ⫺33%, and ⫺50% for
years 0–1, 1–2, 2–3, and 3–4, respectively. During the
double-blind period, rates of overall infections by cortico-
steroid use at baseline were similar regardless of
whether patients received placebo or belimumab (Table
2). Compared with year 1 of exposure, rates of overall
and serious and/or severe infections were decreased
during the following 3 years of belimumab treatment
regardless of the use of corticosteroids. Serious and/or
severe infection rates were, however, 2.5-fold higher in
patients receiving corticosteroids than in those receiving
no corticosteroids at baseline.
Baseline demographic data, including SLE dis-
ease activity, autoantibodies, low complement levels,
and B cell subsets, were evaluated in patients treated
with prednisone and/or MMF as compared with those
not treated with prednisone and/or MMF. There were
no significant differences in distribution across treat-
ment groups. In patients treated with MMF and those
not treated with MMF at baseline, SLE disease activity,
autoantibodies, low complement levels, and B cell sub-
sets were similar, except that patients treated with MMF
were more likely to have renal disease with proteinuria
⬎1.0 gm/24 hours. In patients treated with prednisone
and those not treated with prednisone at baseline, there
were no significant differences in the Safety of Estrogens
in Lupus Erythematosus National Assessment version
of the Systemic Lupus Erythematosus Disease Activity
Index, the physician’s global assessment scores, and
SLE plasma cells. There were, however, greater propor-
tions of patients treated with prednisone than those not
treated with prednisone who had British Isles Lupus
MERRILL ET AL
Assessment Group A scores (renal and vasculitis), auto-
antibodies, and low complement levels at baseline, but
patients treated with prednisone had a lower number of
B cells.
Malignancies. Malignancies (excluding nonmela-
noma skin cancers) occurred at a rate of 0.34/100 patient-
years (95% CI 0.09–0.88) during the 4-year exposure
period: 2 solid organ cancers (lung cancer with metas-
tases to bone and bone marrow in year 2, and breast
cancer in year 3) and 2 hematologic malignancies (B cell
lymphoma in year 2, and multiple myeloma in year 4)
were reported in 4 patients. Seven nonmelanoma skin
cancers were reported during the 4-year exposure pe-
riod: 3 squamous cell carcinomas (1 in year 1, and 2
in year 4) and 4 basal cell carcinomas (2 in year 2, 1 in
year 3, and 1 in year 4); the average age of these patients
was 61.7 years (range 53–72 years).
Abnormal laboratory findings (grade 3 or 4).
Rates of grade 3 or 4 abnormal laboratory findings were
similar with placebo and belimumab during the double-
blind portion of the study (23). In year 1 of exposure,
grade 3 or 4 lymphopenia and increased prothrombin
time (PT) occurred in ⱖ14% of patients (Table 3). In
the long-term continuation study, laboratory testing of
PT time was not required and was only performed if the
investigators deemed it to be clinically indicated. Most
patients (75–100%) with elevated PT (grades 3/4) were
receiving warfarin. The remaining grade 3 or 4 abnormal
laboratory findings occurred in ⱕ6.9% of patients and
either remained stable or declined through the following
3 years of treatment. Other grade 3 or 4 abnormal
laboratory findings (liver function, clinical chemistry,
LONG-TERM SAFETY PROFILE OF BELIMUMAB 3371

Table 3. Grade 3 or 4 abnormal laboratory findings occurring during belimumab exposure (2%/100
patient-years in any year interval) and immunoglobulin changes
Year 1 Year 2 Year 3 Year 4
(n ⫽ 424) (n ⫽ 339) (n ⫽ 274) (n ⫽ 248)
% with grade 3 or 4 abnormal laboratory findings*
White blood cells (⬍2,000/mm3) 3.3 4.2 2.6 2.0
Neutrophils (⬍1,000/mm3) 6.4 5.6 4.4 4.9
Lymphocytes (⬍500/mm3) 22.0 19.3 14.3 13.4
Hemoglobin (ⱕ8.0 gm/dl) 2.6 1.5 0.4 1.2
Prothrombin time (⬎1.5⫻ upper limit of normal)† 14.3 12.0 24.3 17.9
Proteinuria (24-hour collection; ⱖ2 gm/24 hours) 6.9 3.6 1.5 1.2
Hypogammaglobulinemia (ⱕ399 mg/dl)‡ 1.9 1.2 1.1 1.2
Median % change in Ig levels from baseline
IgG –9.1 –10.9 –10.2 –12.9
IgA –11.9 –14.2 –15.4 –17.9
IgM –25.9 –35.6 –41.2 –46.6
IgE –28.7 –35.7 –40.0 –45.5

* Values in parentheses represent grade 3 abnormal laboratory values and are provided as a reference.
† During the long-term continuation period, the protocol did not require regularly scheduled prothrombin
time assessments. Assessments were performed only when the investigators deemed it to be clinically
indicated. At years 1–4, a total of 421, 274, 37, and 39 patients, respectively, were assessed. Of the patients
with grades 3/4 prothrombin time, 75%, 85%, 100%, and 100% were receiving warfarin at years 1–4,
respectively.
‡ At years 1–4, a total of 418, 337, 272, and 247 patients, respectively, were assessed.

and electrolytes) occurred in ⬍2% of patients and did
not increase over time (data not shown).
Immunoglobulins. During 4 years of belimumab
exposure, the median levels of IgG and IgA declined
slightly after year 1 compared with baseline and re-
mained stable over the following 3 years (Table 3). The
median IgM and IgE levels declined further after
year 1 of therapy. The frequency of grade 3 hypogamma-
globulinemia (250–399 mg/dl) was 1.9% in year 1, did
not change from years 2 to 4 (Table 3) and was not
associated with increases in infection rates (including
severe and/or serious infections [data not shown]). No
patients experienced grade 4 hypogammaglobulinemia
(⬍250 mg/dl) or discontinued belimumab due to hypo-
gammaglobulinemia.
DISCUSSION
This report describes safety data in patients with
moderate-to-severe SLE disease activity at baseline de-
spite receiving standard therapy for the disease who
were exposed to belimumab for 4 years, which is the
longest reporting period from an ongoing trial of a
biologic agent in patients with SLE. The long-term
continuation study allowed for standard therapy to con-
tinue as needed along with belimumab, with no thera-
peutic modifications mandated to the physicians or their
patients. The demographic and other baseline charac-
teristics of the population of patients who elected to
participate in the long-term continuation study were
similar to those of the study population enrolled in the
double-blind trial, which addresses the risk of selection
bias at the start of the study (23). It can, however, be
expected that the population of patients who entered the
long-term study and continued throughout the 4 years
may have been enriched in individuals who responded
best to belimumab or tolerated this treatment better.
During the 4 years of belimumab treatment, no
new safety concerns emerged. Interpretation is, how-
ever, limited because there was no control group in the
long-term continuation study. In 2 large phase III
placebo-controlled studies of belimumab that lasted for
52 or 76 weeks, the incidence rates of AEs (including
serious AEs and infections) were similar in the beli-
mumab and placebo groups (25,26). The data in the
present long-term analysis are consistent with the find-
ings in the phase II and phase III placebo-controlled
trials; that is, no specific patterns of infections and no
increase in the incidence or severity of AEs were
observed (23,25,26).
Individuals with SLE have a 2–5-fold increased
risk of death as compared with the general population
(15,16). The most common causes of death in patients
with SLE are cardiovascular disease, infections (espe-
cially pneumonia), renal disease, and complications of
lupus disease activity (7,16). The mortality rate of
0.4/100 patient-years observed in the long-term contin-
3372
uation study of belimumab is less than the rate of 1.63
reported in the literature for SLE patients (16), although
the historical rate may be an overestimate, given de-
creases in SLE mortality rates seen over time, and
patients in a clinical trial may be followed up and
monitored differently from those in a practice setting
(27). Notably, there did not appear to be an increased
risk of death associated with belimumab treatment over
the 4-year period.
The malignancies (excluding nonmelanoma skin
cancer) occurring in patients in the present study are
consistent with those expected in an SLE population
largely composed of women, and the malignancy rate
(0.34/100 patient-years) is similar to the background rate
reported in patients with SLE (0.53/100 patient-years)
(12). In the long-term continuation study, serious infu-
sion reactions were rare, and the discontinuation rate
due to AEs or infections was low and declined over time.
Although this may reflect a survivor bias, and patients
who may have been more prone to AEs may have been
depleted from the study population earlier on, the data
suggest that most patients avoided major AEs with
belimumab for ⱖ1 year, and once they reached the
1-year milestone, the likelihood of continuing to do well
for up to 4 years was increased.
Several novel targeted biologic therapies have
been studied for the treatment of SLE, and it could be
hoped that targeted immune modulators may be safer
than global immunosuppression, especially with regard
to serious infections (28,29). Mycophenolate mofetil
has been used to prevent rejection of transplanted tissue
and to treat patients with SLE and lupus nephritis
(6,30,31). Although it is an effective drug, MMF has
been associated with an increased risk of infections and
gastrointestinal disorders in clinical trials (30,32,33). In
comparison with other background treatments (e.g.,
non-MMF immunosuppressants or no immunosuppres-
sants), the use of MMF at baseline in the present long-term
belimumab study was associated with increased rates
of serious and/or severe infections over the 4 years of
treatment, but this was not reflected in the overall
infection rates or Ig levels. High-dose corticosteroids are
associated with significant morbidity, including osteo-
porosis, osteonecrosis, metabolic disorders, infections,
weight gain, and hyperlipidemia (3,4). Similar to the use
of MMF, there was an increased risk of serious and/or
severe infections, but not overall infections, in patients
in the present study who were taking corticosteroids at
baseline. The overall use of immunosuppressive agents
was fairly constant over 4 years, whereas corticosteroid
use decreased.
MERRILL ET AL
In this long-term continuation analysis, beli-
mumab was safe and generally well-tolerated over 4
years of treatment in combination with standard therapy
for SLE. An important finding of this study was the
ability to safely maintain a significant proportion of the
original treatment population on combination treatment
for this prolonged period of time. Given the heterogen-
eity of the SLE population and the propensity of many
immunosuppressants to cause toxicities in the long term,
this provides initial groundwork upon which to build
more effective and more tolerable combination treat-
ment strategies for SLE.
ACKNOWLEDGMENTS
The authors wish to thank Shannon Benedetto (Hu-
man Genome Sciences, Inc.) and Geoff Marx (BioScience
Communications, New York, NY) for editorial support.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Merrill had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Merrill, Ginzler, Wallace, McKay,
Condemi, Zhong, Pineda, Klein, Freimuth.
Acquisition of data. Merrill, Ginzler, Wallace, McKay, Lisse, Aranow,
Wellborne, Burnette, Condemi, Zhong, Pineda, Freimuth.
Analysis and interpretation of data. Merrill, Ginzler, Wallace, McKay,
Lisse, Aranow, Wellborne, Burnette, Condemi, Zhong, Pineda, Klein,
Freimuth.
Medical monitor. Klein.
ROLE OF THE STUDY SPONSOR
Human Genome Sciences, Inc. was involved in the concep-
tion, design, implementation, and supervision of the study, the data
analysis and interpretation, the statistical analysis, and the manuscript
drafting, revision, and approval. GlaxoSmithKline was involved in the
design of the study and the manuscript drafting, revision, and approval.
Human Genome Sciences, Inc. and GlaxoSmithKline agreed to submit
the manuscript for publication and approved the content of the
manuscript. Editorial assistance in the development of the initial draft
was provided by Shannon Benedetto (Human Genome Sciences, Inc.).
Editorial support throughout the submission process was provided
by Geoff Marx (BioScience Communications, New York, NY) and
was funded by Human Genome Sciences, Inc. and GlaxoSmithKline.
Publication of this article was contingent upon the approval of all of
the authors as well as the approval of Human Genome Sciences, Inc.
and GlaxoSmithKline.
REFERENCES
1. Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet
J Rare Dis 2006;1:6.
2. Pisetsky DS. Systemic lupus erythematosus: epidemiology, pathol-
ogy, and pathogenesis. In: Klippel JH, Crofford LJ, Stone JH,
LONG-TERM SAFETY PROFILE OF BELIMUMAB
Weyand CM, editors. Primer on the rheumatic diseases. 12th ed.
Atlanta: Arthritis Foundation; 2001. p. 329–35.
3. Chatham WW, Kimberly RP. Treatment of lupus with cortico-
steroids. Lupus 2001;10:140–7.
4. Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in
systemic lupus erythematosus and its association with cortico-
steroids. Arthritis Rheum 2000;43:1801–8.
5. Bernatsky S, Joseph L, Boivin JF, Gordon C, Urowitz M, Gladman
D, et al. The relationship between cancer and medication expo-
sures in systemic lupus erythaematosus: a case-cohort study. Ann
Rheum Dis 2008;67:74–9.
6. Karim MY, Alba P, Cuadrado MJ, Abbs IC, D’Cruz DP,
Khamashta MA, et al. Mycophenolate mofetil for systemic lupus
erythematosus refractory to other immunosuppressive agents.
Rheumatology (Oxford) 2002;41:876–82.
7. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla
P, et al, the European Working Party on Systemic Lupus Erythem-
atosus. Morbidity and mortality in systemic lupus erythematosus
during a 10-year period: a comparison of early and late manifes-
tations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;
82:299–308.
8. Goldblatt F, Chambers S, Rahman A, Isenberg DA. Serious
infections in British patients with systemic lupus erythematosus:
hospitalisations and mortality. Lupus 2009;18:682–9.
9. Campbell R Jr, Cooper GS, Gilkeson GS. Two aspects of the
clinical and humanistic burden of systemic lupus erythematosus:
mortality risk and quality of life early in the course of disease.
Arthritis Rheum 2008;59:458–64.
10. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L,
Simantovet R, et al. Prevalence and correlates of accelerated
atherosclerosis in systemic lupus erythematosus. N Engl J Med
2003;349:2399–406.
11. Urowitz MB, Gladman D, Ibanez D, Fortin P, Sanchez-Guerrero
J, Bae S, et al, and the Systemic Lupus International Collaborating
Clinics. Accumulation of coronary artery disease risk factors over
three years: data from an international inception cohort. Arthritis
Rheum 2008;59:176–80.
12. Bernatsky S, Boivin JF, Joseph L, Rajan R, Zoma A, Manzi S,
et al. An international cohort study of cancer in systemic lupus
erythematosus. Arthritis Rheum 2005;52:1481–90.
13. Bernatsky S, Ramsey-Goldman R, Isenberg D, Rahman A, Dooley
MA, Sibley J, et al. Hodgkin’s lymphoma in systemic lupus
erythematosus. Rheumatology (Oxford) 2007;46:830–2.
14. Parikh-Patel A, White RH, Allen M, Cress R. Cancer risk in a
cohort of patients with systemic lupus erythematosus (SLE) in
California. Cancer Causes Control 2008;19:887–94.
15. Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality
studies in systemic lupus erythematosus: results from a single
center. I. Causes of death. J Rheumatol 1995;22:1259–64.
16. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman
DD, et al. Mortality in systemic lupus erythematosus. Arthritis
Rheum 2006;54:2550–7.
17. 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.
18. Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern
WG, et al. Generation and characterization of LymphoStat-B, a
3373
human monoclonal antibody that antagonizes the bioactivities of
B lymphocyte stimulator. Arthritis Rheum 2003;48:3253–65.
19. 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.
20. 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.
21. 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.
22. Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ,
et al. A role for B lymphocyte stimulator in systemic lupus
erythematosus. J Immunol 2001;166:6–10.
23. 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.
24. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D,
et al, for the 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.
25. Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA,
Jimenez RE, et al. Efficacy and safety of belimumab in patients
with active systemic lupus erythematosus: a randomised, placebo-
controlled, phase 3 trial. Lancet 2011;377:721–31.
26. National Institute of Allergy and Infectious Diseases. Division
of Microbiology and Infectious Diseases (DMID) Adult Toxicity
Tables. 2007. URL: http://www.niaid.nih.gov/labsandresources/
resources/dmidclinrsrch/pages/toxtables.aspx.
27. Ippolito A, Petri M. An update on mortality in systemic lupus
erythematosus. Clin Exp Rheumatol 2008;26 Suppl 51:S72–9.
28. Karim MY, Pisoni CN, Khamashta MA. Update on immunother-
apy for systemic lupus erythematosus—what’s hot and what’s not!
Rheumatology (Oxford) 2009;48:332–41.
29. Lateef A, Petri M. Biologics in the treatment of systemic lupus
erythematosus. Curr Opin Rheumatol 2010;22:504–9.
30. Appel GB, Contreras G, Dooley DA, Ginzler EM, Isenberg D,
Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide
for induction treatment of lupus nephritis. J Am Soc Nephrol
2009;20:1103–12.
31. Ginzler EM, Wofsy D, Isenberg D, Gordon C, Lisk L, Dooley MA,
for the ALMS Group. Nonrenal disease activity following myco-
phenolate mofetil or intravenous cyclophosphamide as induction
treatment for lupus nephritis: findings in a multicenter, prospec-
tive, randomized, open-label, parallel-group clinical trial. Arthritis
Rheum 2010;62:211–21.
32. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill
JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide
for lupus nephritis. N Engl J Med 2005;353:2219–28.
33. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Induction and
maintenance therapy for lupus nephritis: a systematic review and
meta-analysis. Lupus 2010;19:703–10.