A 5-Year Prospective Observational Registry to Assess Adverse Events of Interest and Effectiveness in Adults With Active, Autoantibody-Positive Systemic Lupus Erythematosus Treated With or Without BENLYSTA™ (Belimumab)
Conditions: Systemic Lupus Erythematosus
Sponsor: GlaxoSmithKline

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HGS1006-C1124 (BEL116543) 
 
 
 
CLINICAL PROTOCOL HGS1006-C1124 
Protocol Amendment: 05 
Date: 25 May 2022 
 
 
TITLE OF STUDY:  
 
A 5-Year Prospective Observational Registry to Assess Adverse Events of Interest and 
Effectiveness in Adults with Active, Autoantibody-Positive Systemic Lupus 
Erythematosus Treated with or without BENLYSTA™ (belimumab) 
 
 
 
STUDY SPONSOR: 
GlaxoSmithKline, LLC 
 
5 Crescent Drive 
 
Philadelphia, Pennsylvania 19112 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies.  All rights reserved.   
Unauthorised copying or use of this information is prohibited. 
 
 

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Revision Chronology for HGS1006-C1124 (BEL116543) 
Document Identifier 
Date 
Document* 
Global 
14 August 2012 
Original 
Global 
01 November 2012 
Amendment No. 01 
Local 
2013N183013_00 
10 December 2013 
Local Addendum No. 01 for 
Sweden 
Global 
2017N316452_00 
19 June 2017 
Amendment No. 02 
Global 
2017N316452_01 
12 March 2018 
Amendment No. 03 
Global 
2017N316452_02 
25 Nov 2020 
Amendment No. 04 
Global 
TMF-14148167 
25 May 2022 
Amendment No. 05 
*A Summary of Modifications document which provides a detailed list of changes for the amendment/addendum is available 
upon request. 
 
Milestones 
Milestone 
Planned Date 
Registration in the EU PAS register 
16 October 2013 
Start of data collection 
February 2013 
End of data collection 
2025 
Interim Report 1 
28 February 2014 
Interim Report 2 
28 February 2015 
Interim Report 3 
28 February 2016 
Interim Report 4 
28 February 2017 
Interim Report 5 
28 February 2018 
Interim Report 6 
28 February 2019 
Interim Report 7 
28 February 2020 
Interim Report 8 
28 February 2021 
Interim Report 9 
28 February 2022 
Interim Report 10 
28 February 2023 
Interim Report 11 
28 February 2024 
Interim Report 12 
28 February 2025 
Final Report  
28 February 2026 
 

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Investigator Agreement 
I will provide copies of the protocol, any subsequent amendments and access to all information 
furnished by the sponsor to study personnel under my supervision. I will discuss this material 
with them to ensure that they are fully informed about the investigational study agent and the 
study protocol. I agree to conduct this clinical trial according to the protocol described herein, 
except when mutually agreed to in writing with the sponsor. I also agree to conduct this study 
in compliance with guidelines for Good Pharmacoepidemiology Practices (GPP) as defined by 
the International Society of Pharmacoepidemology (ISPE) all applicable national, state, and 
local regulations, as well as the requirements of the appropriate Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and any other institutional requirements. 
 
 
Principal Investigator: 
 
 
 
Signature 
 
 
 
 
 
 
 
 
Date (dd mmm yy) 
 
 
 
Name (please type or print) 
 
 
 
Institution 
 
 
 
Address (must include country name) 
 
 
 
 
 
 
 
 

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Study Synopsis 
Title of the Study: A 5-Year Observational Prospective Registry to Assess Adverse Events of 
Interest and Effectiveness in Adults with Active, Autoantibody-Positive Systemic Lupus 
Erythematosus Treated with or without BENLYSTA™ (belimumab) 
Clinical Development Phase: 4 
Objectives: 
Primary Objective 
To evaluate the incidence of the following adverse events of special interest (AESI) over 5 years 
in adults with active autoantibody-positive systemic lupus erythematosus (SLE) who are treated 
with or without BENLYSTA: 
• Malignancies (excluding non-melanoma skin cancers) 
• Mortality 
• Opportunistic infections and other infections of interest (Appendix 1) 
• Non-melanoma skin cancers (NMSC)  
• Selected serious psychiatric events (Appendix 2) 
• Serious infections 
 
Other Objectives 
To evaluate the following effectiveness measures in adults with active autoantibody-positive 
SLE who are treated with or without BENLYSTA: 
• Organ damage as assessed by SLICC/ACR Damage Index (Appendix 5) 
• Concomitant SLE medications including steroids 
• Hospitalizations 
 
Inclusion Criteria: 
Patients enrolled in the registry must meet the following inclusion criteria: 
1. Males or females age 18 or older. 
2. Have a clinical diagnosis of active SLE.  
3. Current or history of autoantibody-positive SLE. 
4. Must be treated with SLE therapy including BENLYSTA and/or immunosuppressants 
(eg, azathioprine, methotrexate, cyclophosphamide, mycophenolate, and biologics). 
5. Have the ability to understand the requirements of the study, provide written informed 
consent, including consent for the use and disclosure of research-related health 
information, and comply with the study data collection procedures. 

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Exclusion Criteria: 
Patients will be excluded from participating in the registry if they meet any of the following 
exclusion criteria: 
1. Treatment with an investigational drug within one year of enrollment. Investigational drug 
applies to any drug not approved for sale in the country it is being used. 
2. Currently enrolled in a placebo-controlled BENLYSTA (belimumab) clinical trial or a 
continuation protocol where belimumab is used as an investigational agent. 
3. Patients who have a history of BENLYSTA exposure, but are not currently receiving 
BENLYSTA. 
4. Patients only receiving an anti-malarial for SLE. 
5. Patients only receiving steroids for SLE. 
 
Study Design: 
This is a multi-center, prospective, observational cohort study to evaluate the incidence of 
adverse events of special interest (AESI) and effectiveness in patients with active, autoantibody-
positive SLE treated with and without BENLYSTA. BENLYSTA refers to any commercially 
available formulation of belimumab. BENLYSTA formulation, intravenous (IV) or 
subcutaneous (SC), will be recorded for each patient in the protocol database. Patients will 
receive BENLYSTA at the discretion of their physician. All treatment decisions are at the 
discretion of the patient and their healthcare provider and are not mandated by study design or 
protocol. All assessments are intended to be performed at the time of clinical encounters, per 
routine care. Patients will be enrolled into 1 of 2 cohorts, those who, at baseline, are receiving 
or initiating BENLYSTA (BENLYSTA cohort) or are not receiving BENLYSTA (comparison 
cohort). BENLYSTA or comparison cohort patients may be either treatment initiators or current 
users. Treatment initiators are defined as those patients who have initiated immunosuppressants 
and/or BENLYSTA in the last 2 months, while the current users are those who have received 
immunosuppressants and/or BENLYSTA for ≥2 months at the time of entry into the registry. 
The study will enroll approximately 3,000 patients, approximately 2,000 in the BENLYSTA 
cohort and 1,000 in the comparison cohort. Enrollment is expected to occur primarily in the US, 
Canada, and Europe. Each patient will be followed for 5 years contributing a total of 
approximately 7,773 patient years in the BENLYSTA cohort and 3,886 patient years in the 
comparison cohort, respectively, assuming a 10% annual patient drop-out rate and not 
accounting for crossover.  
Data will be collected at enrollment and at approximately 6 month intervals for 5 years (60 
months). All patients will be assessed for AESI including serious infections, opportunistic 
infections and other infections of interest, malignancies (including NMSC), selected serious 
psychiatric events and mortality. Organ damage as assessed by SLICC/ACR Damage Index 
(SDI), concomitant SLE medications including steroids, demography (eg, age, gender, 
race/ethnicity; where allowed by local regulation), smoking history, alcohol use, 

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hospitalizations, and disease activity of SLE will also be evaluated in all patients at defined 
visits (see Table 6-1). Adverse events not collected in this study should be reported in 
accordance with the laws and regulations for marketed products in the country in which the 
event occurred. 
Primary Endpoints: 
Incidence of the following adverse events of special interest (AESI): 
• Malignancies (excluding non-melanoma skin cancers) 
• Mortality 
• Opportunistic infections and other infections of interest (Appendix 1) 
• Non-melanoma skin cancers (NMSC)  
• Selected serious psychiatric events (Appendix 2) 
• Serious infections 
 
Effectiveness Endpoints: 
• Organ damage as assessed by SLICC/ACR Damage Index (Appendix 5) 
• Concomitant SLE medications including steroids 
• Hospitalizations 
 
Sample Size Consideration: 
This registry will enroll approximately 3,000 patients, approximately 2,000 receiving or 
initiating BENLYSTA plus standard of care (BENLYSTA cohort) and 1,000 standard of care 
only (comparison cohort). Each patient will be followed for 5 years, contributing a total of 
approximately 7,773 patient years in the BENLYSTA cohort and 3,886 patient years in the 
comparison cohort, respectively), assuming a 10% annual patient drop-out rate and not 
accounting for crossover.  
The registry will allow the difference in mortality rate in the BENLYSTA cohort and 
comparison cohort to be established with a 95% CI of +/-0.32 per 100-subject years, based on 
an estimated mortality rate of 0.68 per 100-subject years in both treatment groups (Table 1). 
The estimated mortality rate was based on the mortality rate in the pooled IV primary safety 
database in SLE subjects derived from 3 randomized, double-blind, IV placebo-controlled trials, 
referred to as IV SLE Controlled, Repeat Dose (CRD) studies (ie, integrated database of 
LBSL02 [placebo-controlled treatment phase only], HGS1006-C1056, and HGS1006-C1057) 
for all subjects (IV belimumab and placebo) adjusted for subject years. The precision of the 
rates of the AESI are provided in the table below: 

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Table 1 
Precision of differences in AE rates estimated from a total of 7,773 
patient years in the BENLYSTA cohort and 3,886 patient years in the 
comparison cohort, respectively  
Adverse Events 
Reference Rate1 
(per 100-patient years) 
95% Confidence Interval for difference 
in AE rates2 (per 100-patient years) 
All deaths 
0.68 
±0.32 
Serious infection 
5.80  
±0.93  
Opportunistic infection 
0.136  
±0.14 
Malignancy excl. NMSC 
0.226 
±0.19  
NMSC 
0.226 
±0.19 
Selected serious psychiatric events 
0.410 
±0.25 
1 
The reference AE rates were based on the AE rates in the pooled IV primary safety database derived from 
the IV SLE CRD studies (LBSL02, HGS1006-C1056, HGS1006-C1057) and adjusted for subject years.  
2 
Assuming that the AE rates in BENLYSTA and the control groups were the same as the reference rate. 
 
Analysis of Primary Endpoints: 
In addition to analyses that consider initial treatment group (BENLYSTA cohort vs comparison 
cohort), analyses that specifically account for changes in therapy (in either group) by 
considering a variety of risk windows will be employed. These analyses will attribute events to 
BENLYSTA treatment if they occur within the designated risk windows for BENLYSTA 
exposure and to comparison treatment otherwise. These analyses will allow for a registry patient 
to contribute person-time to both BENLYSTA treatment, and comparison treatment and as a 
result, will specifically account for treatment switching to BENLYSTA or from BENLYSTA. 
Switching between BENLYSTA and comparison treatment will be taken into account in a 
number of ways in the analysis and will be further defined within the statistical analysis plan. 
No new analyses for changing between BENLYSTA formulation or stratifying by BENLYSTA 
formulation are planned. Planned analyses are outlined below; all analyses will be detailed in 
the statistical analysis plan. 
 
 
 
 
 
 

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• Analysis by initial treatment group of rate per person years of observation time. 
• Analysis by initial treatment group of rate per person years of exposure where 
BENLYSTA exposure ends 14 weeks (approximately 5 half-lives) after cessation of 
treatment. 
• For serious psychiatric events, BENLYSTA exposure is all time on treatment with 
BENLYSTA ending 14 weeks (approximately 5 half-lives) after cessation of treatment, 
with all remaining treatment time attributed to the comparison cohort.  
• For serious infections, opportunistic infections and other infections of interest, 
BENLYSTA exposure is all time on treatment with BENLYSTA ending 6 months after 
cessation of treatment, with all remaining treatment time attributed to the comparison 
cohort.  
• For NMSC and malignancies excluding NMSC, analysis will be performed where all 
events will be attributed to BENLYSTA if the patient was ever exposed to BENLYSTA 
treatment prior to the event and attributed to the comparison cohort otherwise (ie, once 
exposed, always at risk). 
• Mortality will be analyzed applying all the above-mentioned risk windows (eg, 14 weeks,  
6 months, and ever-exposed).  
• Other risk windows (including risk windows for comparison treatment) may also be 
assessed and defined in the statistical analysis plan. 
 
Additional safety analysis will be performed comparing BENLYSTA treatment initiators with 
patients from the comparison cohort that start or switch an immunosuppressant and that have 
comparable background medication and treatment history. Subgroup analysis will be performed 
that will include but not be limited to analysis of patients with positive anti-dsDNA and low 
complement at baseline, patients with SLEDAI 2000 score at baseline (<10 vs ≥10), SDI (0 vs 
≥1), steroid use (yes vs no; ≤7.5 mg/day vs >7.5 mg/day), immunosuppressant use (yes vs no; 
mycophenolate vs immunosuppressant other than mycophenolate), region (US/Canada vs 
Europe vs other), and race (black race vs other). Safety analyses will be adjusted for potential 
confounding factors (Appendix 7) through propensity score methods or other appropriate 
statistical methods. No new analyses for changing between BENLYSTA formulation or 
stratifying by BENLYSTA formulation are planned. Further details of the safety analyses will 
be described in the statistical analysis plan. 
Analysis of Effectiveness Endpoints: 
For any effectiveness endpoint analyses performed, methods to reduce the potential impact of 
confounding may be employed. These methods could include subgroup analysis, modeling 
adjusting for baseline and/or other confounding variables, or patient matching techniques like 
propensity score analysis. Furthermore, analyses considering changes in BENLYSTA use over 
time (eg, on or off treatment, but not changes between BENLYSTA formulations) in order to 
assess BENLYSTA effectiveness, as well as evaluate how these endpoints vary in response to 
BENLYSTA treatment will be assessed and further explored as appropriate. These analyses 
will be described in the statistical analysis plan.  

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Study Calendar: 
See Table 6-1 for data collection time points. 

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Table of Contents 
Revision Chronology for HGS1006-C1124 (BEL116543) ........................................................ 2 
Milestones ................................................................................................................................... 2 
Investigator Agreement .............................................................................................................. 3 
Study Synopsis ........................................................................................................................... 4 
Table of Contents...................................................................................................................... 10 
List of Tables ............................................................................................................................ 12 
List of Abbreviations ................................................................................................................ 13 
1 
Background ................................................................................................................... 15 
1.1 Disease Background Relevant to the Registry ............................................................. 15 
1.2 BENLYSTA Background Relevant to the Registry ..................................................... 17 
1.3 Rationale for the Registry ............................................................................................. 20 
2 
Study Design................................................................................................................. 21 
3 
Objectives ..................................................................................................................... 21 
4 
Outcome Definitions and Measures ............................................................................. 22 
5 
Inclusion and Exclusion Criteria .................................................................................. 23 
5.1 Inclusion Criteria .......................................................................................................... 23 
5.2 Exclusion Criteria ......................................................................................................... 24 
6 
Data Collection ............................................................................................................. 24 
6.1 Study Enrollment Evaluations ...................................................................................... 24 
6.2 On Study Evaluations ................................................................................................... 25 
6.3 Registry Completion ..................................................................................................... 25 
6.4 Discontinuation and Lost to Follow-Up ....................................................................... 25 
7 
Adverse Events ............................................................................................................. 29 
7.1 Definitions .................................................................................................................... 29 
7.2 Reporting Adverse Events ............................................................................................ 29 
7.2.1 
Adverse Events of Special Interest ............................................................... 29 
7.2.2 
Serious AESI and Deaths ............................................................................. 30 
7.2.3 
Other Adverse Events ................................................................................... 30 
7.3 Suicidality ..................................................................................................................... 30 
7.4 Investigator Evaluation of Adverse Events .................................................................. 31 
7.5 Follow-Up of Adverse Events of Special Interest ........................................................ 32 
7.6 Reporting Serious Adverse Events to the Regulatory Authorities and Institutional 
Review Board/Ethics Committee ........................................................................... 32 
8 
Data Analysis ................................................................................................................ 32 
8.1 General Statistical Considerations ................................................................................ 32 

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8.2 Sample Size Consideration ........................................................................................... 32 
8.3 Endpoints and Analysis ................................................................................................ 33 
8.3.1 
Primary Endpoints ........................................................................................ 33 
8.3.2 
Analysis of Primary Endpoints ..................................................................... 34 
8.3.3 
Effectiveness Endpoints and Analysis .......................................................... 35 
9 
Scientific Advisory Committee (SAC) ......................................................................... 35 
10 
Study Limitations ......................................................................................................... 35 
11 
Study Administration .................................................................................................... 36 
11.1 
Informed Consent ................................................................................................... 36 
11.2 
Institutional Review Board Review/Independent Ethics Committee Review and 
Approval ................................................................................................................. 36 
11.3 
Protocol Revisions .................................................................................................. 36 
11.4 
Data Management ................................................................................................... 36 
11.5 
Study Conduct ........................................................................................................ 37 
11.6 
Retention of Records .............................................................................................. 37 
11.7 
Publication Policy ................................................................................................... 37 
11.8 
Study or Study Site Termination ............................................................................ 38 
References ................................................................................................................................ 39 
List of Appendices .................................................................................................................... 44 
 
 
 

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List of Tables 
Table 1 
Precision of differences in AE rates estimated from a total of 7,773 
patient years in the BENLYSTA cohort and 3,886 patient years in the 
comparison cohort, respectively ..................................................................... 7 
Table 1-1  
Adverse Events of Special Interest (IV SLE CRD) 1 .................................... 17 
Table 6-1  
Study calendar ............................................................................................... 27 
Table 8-1  
Precision of differences in AE rates estimated from a total of 7773 
patient years in the BENLYSTA cohort and 3886 patient years in the 
comparison cohort, respectively ................................................................... 33 
 

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List of Abbreviations 
ACR 
American College of Rheumatology 
AE 
adverse Event 
AESI 
adverse Events of Special Interest 
BAFF 
B cell activating factor belonging to the TNF family 
BCG 
Bacillus Calmette-Guérin 
BLyS 
B lymphocyte stimulator 
CI 
Confidence Interval 
CMV 
cytomegalovirus 
CRD 
controlled repeat dose 
CRF 
case report form 
eCRF 
electronic case report form 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices 
GSK 
GlaxoSmithKline 
HGS 
Human Genome Sciences 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HPV 
human papillomavirus 
ICH 
International Conference on Harmonisation 
ICSR 
Individual Case Safety Reports 
IEC 
Independent Ethics Committee 
IPSE 
International Society of Pharmacoepidemology 
IRB 
Institutional Review Board 
IV 
intravenous 
NHL 
non-Hodgkin’s lymphoma 
NMSC 
non-melanoma skin cancer 
PML 
Progressive multifocal leukoencephalopathy 
PSRHQ 
possible suicidality-related history questionnaire 
PSRQ 
possible suicidality-related questionnaire 
SABLE 
Safety And effectiveness of Belimumab in Systemic Lupus Erythematosus 
Registry 
SAC 
Scientific Advisory Committee 
SAE 
serious adverse event 
SDI 
SLICC/ACR Damage Index 
SELENA 
Safety of Estrogen in Lupus National Assessment trial 
SIR 
Standardized Incidence Ratio 
SLE 
systemic lupus erythematosus 
SLEDAI 2000 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
TB 
tuberculosis 
TNF 
tumor necrosis factor 

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US 
United States of America 
UTI 
urinary tract infection 
WBC 
white blood cell count 

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1 
Background 
1.1 
Disease Background Relevant to the Registry 
SLE is a chronic debilitating autoimmune disease that primarily affects young women of 
childbearing age, although men, children and teenagers also can develop lupus. SLE is 
characterized by the presence of autoreactive B cells resulting in elevated levels of 
autoantibodies, which directly damage the body’s cells and tissues or form immune complexes 
which cause inflammation and tissue damage. A range of organ systems may be involved 
simultaneously or sequentially. The manifestations of lupus include arthritis, pleuritis, 
pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia, alopecia, 
photosensitivity, and malar rash. Over time, patients with lupus accrue irreversible organ 
damage which contributes to an increased mortality rate in these patients. Despite advances 
over the past 40 years in both diagnosis and treatment, patients with SLE have a 2 - 5-fold 
greater risk of mortality. 
SLE most often develops between the ages of 15 – 44 with an insidious onset (Danchenko et al, 
2006). In the US, the estimated average of the reported prevalence is approximately 10 cases 
per 10,000 persons, representing about 300,000 patients, and the incidence has increased 2.5-
fold between 1950 and 1979 (Uramoto et al, 1999; Somers et al, 2007; Balluz et al, 2001; 
Naleway et al, 2005; Ward, 2004; Helmick et al, 2008). In the European Union, an estimated 
overall average of the reported prevalence is 4 to 5 cases per 10,000 persons (Alamanos et al, 
2003; Benucci et al, 2005; Eilertsen et al, 2006; Gourley et al, 1997; Govoni et al, 2006; 
Gudmundson et al, 1990; Hopkinson et al, 1993; Johnson et al, 1995; Lopez et al, 2003; 
Nightingale et al, 2007; Nossent, 2001; Piette et al, 2004; Samanta et al, 1992; Stahl-Hallengren 
et al, 2000; Voss et al, 1998). Recent studies by Bernatsky et al, have emphasized the increased 
risk of mortality in SLE and have provided data comparing all cause and disease-specific 
relative mortality across groups characterized by age, sex, SLE duration, calendar-year period, 
geographic location, and race (Bernatsky et al, 2006). A 2.4-fold greater risk of mortality (95% 
CI 2.3–2.5) was identified in SLE compared with the general population and there was an 
increased risk of death due to cardiovascular causes, malignancy, infections, and renal disease.  
In an attempt to answer the question as to whether patients with SLE have an increased risk of 
malignancy in comparison to the general population, several large studies have recently been 
conducted. In the Swedish cohort of patients with SLE, Bjornadal et al used hospital discharge 
data to demonstrate an increased relative risk of any malignancy in SLE patients that was 25% 
higher among SLE patients compared to the general population. Of note, this finding was driven 
primarily by the higher incidence of non-Hodgkins lymphoma (NHL) in the SLE population 
which had a relative risk that was 2.86-fold higher (95% CI 1.96, 4.04) than that of the general 
population. These findings have been subsequently confirmed by the Systemic Lupus 
International Collaborating Clinics research group (SLICC) in a larger international multi-
center cohort study. Using Standardized Incidence Ratio (SIR) estimates, a small increase in all 
malignancies combined was observed (SIR, 1.15, 95% CI 1.05, 1.27) for SLE compared to that 
expected for the general population based on data from regional cancer registry linkages 

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(Bernatsky et al, 2005). Similarly, the increased risk for NHL was also demonstrated (SIR, 3.64, 
95% CI 2.63, 4.93) in the SLE population compared to the general population. Unfortunately, 
no investigations have been able to establish the reason for the close association between SLE 
and malignancy. Potential considerations in this regard include abnormal immune activity early 
in the course of the disease, as well as cumulative exposure to immunosuppressive medications. 
In the SLICC international multi-center cohort study, the adjusted Hazard Ratio (HR) for overall 
risk of malignancy after administration of any immunosuppressive drug was 0.82 (95% CI 
0.50 1.36). However, when specifically considering hematological malignancies (Bernatsky et 
al, 2009), there was a suggestion of an increased risk after immunosuppressive drug exposures 
particularly when the medication exposures were lagged by a period of 5 years (adjusted HR 
2.29, 95% CI 1.02-5.15). 
Infections are responsible for morbidity and mortality in 25-50% of SLE patients; they are the 
primary cause of death in SLE patients in developing countries (Alarcón et al, 2001; Cervera et 
al, 1999 and Alarcón, 2006) In a multi-center European study in which 1,000 SLE patients were 
followed for more than 5 years, infections and disease activity were found to be responsible for 
more than half of all deaths. Moreover, patients with SLE have higher rates of infections and 
poorer outcomes compared to the general population (Doria et al, 2008; Petri, 1998). The 
microorganisms responsible for the overwhelming majority of infections in patients with SLE 
are bacteria. However, there are many reports of infections occurring in patients with SLE with 
various outcomes as a consequence of other microorganisms. The increased susceptibility to 
infections may be multifactorial. Disease activity has been shown to be an independent risk 
factor for the occurrence of infections (Petri et al, 1992; Zonana-Nacach et al, 2001) presumably 
because of the abnormal cellular function and complement abnormalities that are more 
pronounced in the affected patients. The use of corticosteroids and other immunosuppressive 
medications has also been associated with the increased occurrence of infections in SLE 
(Gladman et al, 2002; Noel et al, 2001 and Petri et al, 1992). Consequently, the possibility exists 
that an increased occurrence of infections may occur as a consequence of cytokine suppression, 
resulting in multiple cellular functional abnormalities (Boumpas et al, 1993).  
Neuropsychiatric events are well recognized in the SLE population, with a wide incidence 
range. In an international inception cohort study (Hanly, 2007), neuropsychiatric events 
occurred in 28% of subjects near the time of SLE diagnosis, and the incidence of mood disorders 
attributed to SLE ranged from 4% to 13% depending on the attribution model used. Another 
study (Bachen et al, 2009) found the prevalence rates of many psychiatric disorders (major 
depressive disorder, bipolar disorder, panic disorder, etc.) were significantly higher in patients 
with SLE than the general population. The rate of major depression reported in the literature for 
patients with SLE ranges from 22.5%-39.1% (Nery et al, 2007; Brey et al, 2002; Ainiala et al, 
2001). Severe depression requiring hospitalization was found to be 0.26% (14/5371 SLE 
patients in a Swedish cohort followed from 1973 to 2004) (Sundquist et al, 2008). Chronic 
physical illness is also an important risk factor for suicide (Karassa et al, 2003). Patients with 
SLE are at almost 5 times greater risk for suicide than expected (Harris et al, 1994). Suicide 
attempts among SLE patients was 5/300 SLE patients who visited a UK Rheumatology Clinic 

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over a 20-year period (1979-1999) (Karassa et al, 2003) with deaths attributed to suicide ranging 
from 0.23-0.95% (Mok et al, 2008; Nossent et al, 2001; Karassa et al, 2003). 
1.2 
BENLYSTA Background Relevant to the Registry 
BENLYSTA (belimumab) is a recombinant human IgG1λ monoclonal antibody that binds to 
soluble human B-lymphocyte stimulator (BLyS; also known as B cell activating factor 
belonging to the tumor necrosis factor (TNF) family [BAFF] and TNFSF13B) and inhibits its 
biological activity (Baker, 2003).  
The primary safety population, derived from 3 randomized, double-blind, IV placebo-controlled 
trials, referred to as IV SLE Controlled, Repeat Dose (CRD) studies, included safety data from 
the double-blind portion of the two phase 3 studies discussed above (HGS1006-C1056 and 
HGS1006-C1057) as well as the double-blind portion of a Phase 2 study (LBSL02) in 449 
subjects with SLE. A summary of adverse events of special interest in this dataset, the same as 
that to be evaluated in this registry, is provided in Table 1-1. Additional information is provided 
in the Package Insert/Summary of Product Characteristics. 
Table 1-1  
Adverse Events of Special Interest (IV SLE CRD) 1 
 
Placebo 
N = 675 
1 mg/kg 
N = 673 
10 mg/kg 
N = 674 
All Cause Mortality 
 
 
 
Deaths 
3 (0.4%) 
5 (0.7%) 
6 (0.9%) 
Infections and Infestations 
 
 
 
At least 1 Infection AE  
455 (67.4%) 
484 (71.9%) 
477 (70.8%) 
At least 1 serious infection AE  
37 (5.5%) 
48 (7.1%) 
36 (5.3%) 
Opportunistic infections  
- 
1 (0.1%) 
2 (0.3%)  
Malignancies 
 
 
 
Malignancies (all) 
3 (0.4%) 
4 (0.6%) 
3 (0.4%) 
Non-melanoma skin cancers (NMSC) 
1 (0.1%) 
1 (0.1%) 
3 (0.4%) 
Malignancies excluding NMSC 
2 (0.3%) 
3 (0.4%) 
- 
Hematological malignancies 
- 
- 
- 
Psychiatric Disorders 
 
 
 
Psychiatric Disorders (SOC) 
84 (12.4%) 
108 (16.0%) 
107 (15.9%) 
Serious 
3 (0.4%) 
4 (0.6%) 
8 (1.2%) 
Depression/Self-Injury  
34 (5.0%) 
44 (6.5%) 
41 (6.1%) 
Serious 
2 (0.3%) 
3 (0.4%) 
4 (0.6%) 
Suicide 
- 
1 (0.1%) 
1 (0.1%) 
1  Final integrated safety data from 3 IV SLE CRD trials: LBSL02, HGS1006-C1056 and HGS1006-C1057.  
 
With respect to mortality, 14 deaths occurred during the double-blind periods of these 
3 randomized, placebo-controlled SLE trials: 3 (0.4%) in the placebo group, 5 (0.7%) in the 

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1 mg/kg group and 6 (0.9%) in the 10 mg/kg group. An additional death due to respiratory arrest 
was reported more than 3 months after the subject’s participation in a Phase 3 study (1 mg/kg 
group). No single cause of death predominated. Etiologies included infection, cardiovascular 
disease, and suicide. When all IV belimumab SLE studies are considered as of 15 May 2011, 
including long-term studies, the mortality rate per 100 patient-years was 0.56 and 0.43 in 
subjects receiving belimumab and placebo, respectively. 
 
In total, 10 malignant neoplasms, 5 solid organ malignancies and 5 non-melanoma skin cancers, 
were reported in the primary safety population trials. The 5 solid organ malignancies were: 
• Stomach carcinoid (placebo, Day 202) 
• Breast cancer (placebo, 2 months after last dose) 
• Breast cancer (1 mg/kg, Day 102) 
• Cervical cancer (1 mg/kg, Stage 0 in situ, 1.2 years) 
• Ovarian cancer (1 mg/kg, Day 21) 
 
The ovarian cancer ultimately resulted in the death of the patient. There were 5 non-melanoma 
skin cancers: 2 basal cell carcinoma and 3 squamous cell carcinoma of the skin (1 in the placebo 
group, 1 in the 1 mg/kg group, 3 in the 10 mg/kg belimumab group). No solid organ 
malignancies occurred in the 10 mg/kg group. No hematological malignancies were reported in 
the primary safety population. The rate of malignancy, excluding non-melanoma skin cancers, 
across the entire SLE experience as of 15 May 2011 was compared with the malignancy rate in 
SLE patients reported in the literature (Bernatsky et al, 2005). Excluding non-melanoma skin 
cancers is appropriate given that it is known that these are underreported in observational studies 
compared with prospective clinical trials. The malignancy rate per 100 patient-years with 
belimumab is 0.52 (95% CI: 0.34, 0.77) compared with a background rate in SLE subjects of 
0.53 (95% CI: 0.48, 0.59) (Bernatsky et al, 2005). No pattern of malignancies or an increase in 
any particular type of malignancy was identified in subjects receiving belimumab. 
As with other immunomodulating agents, the mechanism of action of belimumab may increase 
the risk for the development of infections. Severe infections, including fatal cases, have been 
reported in SLE patients receiving immunosuppressant therapy, including belimumab.  Serious 
infections occurred in 5% to 7% of subjects across the treatment groups in the primary safety 
population. The top 5 most frequent serious infections (≥ 3 subjects in any treatment group) 
were pneumonia, UTI, cellulitis, bronchitis, herpes zoster, and pyelonephritis; these events 
generally occurred at similar rates between the placebo and the belimumab groups. There was 
no apparent treatment effect or belimumab dose relationship in the incidence of the individual 
serious infections that occurred most frequently. One placebo and 3 belimumab infectious 
deaths were related to sepsis, while 1 belimumab 10 mg/kg death was related to infectious 
diarrhea. Each of these subjects was taking a concomitant steroid and at least 1 other 
immunosuppressant or antimalarial drug. The 2 opportunistic infections in the 10 mg/kg group 
included disseminated cytomegalovirus (CMV) infection on Day 62 that resolved after 52 days 
and Acinetobacter bacteremia on Day 15 that resolved after 28 days. A third potential 

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opportunistic infection occurred in a subject receiving 1 mg/kg belimumab (preferred term: 
pneumonia bacterial infection; verbatim: atypical pneumonia, Acinetobacter lwolfii) on Day 1 
of study so is unlikely to be causally related to belimumab. The infection was treated with 
antibiotics, resolved after 11 days, and was considered not related to belimumab; belimumab 
treatment continued. Overall, in the long-term uncontrolled SLE experience, the incidence of 
infections, including severe and serious infections, remained stable or declined over time. In 
terms of potentially opportunistic infections or other infections of interest in the long-term 
experience as of 09 June 2010, 1 subject had coccidioidomycosis in Year 4 of exposure, and 
another developed a fatal CMV pneumonia also in Year 4 of exposure. Three cases of 
mycobacterial infections (1 latent pulmonary tuberculosis TB [serious], 1 extra pulmonary TB 
[serious], and 1 atypical mycobacterial infection [non-serious]), which had not previously been 
observed in belimumab-treated SLE subjects have been reported. Another case of non-serious 
latent pulmonary TB has also been identified. All mycobacterial infections were reported in 
subjects from countries where TB is endemic. Given that SLE patients are known to be at higher 
risk for tuberculosis (Erdozain et al, 2006), it is not believed that belimumab treatment increases 
the risk of tuberculosis.  
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, including 
fatal cases, has been reported in SLE patients receiving immunosuppressant pharmacotherapy, 
including belimumab. A diagnosis of PML should be considered in any patient presenting with 
new-onset or deteriorating neurological signs and symptoms. The patient should be referred to 
a neurologist or other appropriate specialist for evaluation and if PML is confirmed, 
consideration should be given to stopping immunosuppressant therapy, including belimumab. 
Psychiatric events were reported more frequently with belimumab (16%) than with placebo 
(12%), driven primarily by mild/moderate events of insomnia, depression, and anxiety. Serious 
psychiatric events also were reported at a slightly higher proportion (0.8% with belimumab 
compared with 0.4% with placebo), although the numbers of events were small. There were 2 
completed suicides in belimumab-treated subjects in the primary safety population. A 
composite analysis of depression and self-injury/suicide events was performed that showed 
rates ranging from 5-6% across groups, and serious events were reported in 0.3%, 0.4% and 
0.6% of subjects in the placebo, 1 mg/kg and 10 mg/kg groups, respectively. The majority of 
subjects who reported serious depression or suicidal behavior had a history of depression or 
other serious psychiatric disorders and most were receiving psychoactive medications; in 
addition, these events were not judged to be related to belimumab treatment, nor did they (with 
the exception of the completed suicides) lead to discontinuation of belimumab. 
Although not being evaluated as part of this long-term observational registry, infusion and 
hypersensitivity reactions, including anaphylaxis and death, have been reported in association 
with belimumab. Delay in the onset of acute hypersensitivity reactions has been observed. 
Limited data suggest that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. Belimumab should be administered by healthcare 
providers prepared to manage infusion reactions and anaphylaxis. More information about this 
risk can be found in the package insert/summary of product characteristics. 

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Clinical studies of SC belimumab have demonstrated a safety profile consistent with the 
established safety profile of IV belimumab. The rates of adverse events of special interest, 
including mortality, (primary endpoints) are not reasonably expected to be affected by route of 
administration [Stohl, 2017]. Patients treated with either formulation are therefore eligible to 
participate in this registry.  
1.3 
Rationale for the Registry 
Conservative therapy that is used for non-organ threatening SLE disease may include 
salicylates, nonsteroidal anti-inflammatory drugs, anti-malarials, and low dose corticosteroids. 
Therapies for more severe or organ threatening disease may include high dose corticosteroids, 
methotrexate, leflunomide, azathioprine, cyclosporine, cyclophosphamide, mycophenolate 
mofetil, rituximab, anti-TNFs, intravenous immune globulin, and plasmapheresis used in 
combination with or without medications used for milder disease. While there is concern that 
immunosuppressive medications used in the treatment of SLE are associated with malignancy 
and with increased occurrence of infection, as well as other potentially serious toxicities 
(eg, osteoporosis, osteonecrosis, metabolic abnormalities), the use of immunosuppressant 
medications in SLE may be necessary to reduce the likelihood of disease-related morbidity and 
death as well as to delay and prevent long term damage resulting from some treatments (Urowitz 
et al, 2012).  
While substantial information exists about the safety of BENLYSTA from clinical trials, it is 
important to evaluate the safety of BENLYSTA in real world practice settings over a prolonged 
period of time, particularly with respect to the occurrence of malignancy and serious or 
opportunistic infections. In order to achieve this, it is necessary to gather data on treatment, 
safety and effectiveness in the real world setting over an extended period that can be interpreted 
in the context of other patients not receiving BENLYSTA. It is important to note that differences 
between patients receiving and not receiving BENLYSA, other than BENLYSTA exposure, 
may influence the outcomes and hence confound any planned comparisons in this registry. Such 
factors include baseline disease activity, organ damage, other background treatment, duration 
of disease, etc. The key challenge in this setting is to attempt to minimize such potential 
confounding by selecting appropriate comparison patients as well as collating relevant 
information on potential confounders and making necessary adjustments in the statistical 
models.  
The primary objective of this study is to evaluate the incidence of adverse events of special 
interest (AESI) over 5 years. AESI collected in this study include: serious infections, 
opportunistic infections and other infections of interest, malignancies (including NMSC), 
selected serious psychiatric events and mortality in patients with SLE being treated with and 
without BENLYSTA. Additionally, the study may also evaluate the following effectiveness 
measures in adults with active autoantibody-positive SLE who are treated with or without 
BENLYSTA: organ damage as assessed by SLICC/ACR Damage Index (SDI), concomitant 
SLE medications including steroids, and hospitalizations.  

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2 
Study Design 
This is a multi-center, prospective, observational cohort study to evaluate the incidence of 
adverse events of special interest (AESI) and effectiveness in patients with active, autoantibody-
positive SLE treated with and without BENLYSTA. BENLYSTA refers to any commercially 
available formulation of belimumab. BENLYSTA formulation, intravenous (IV) or 
subcutaneous (SC), will be recorded for each patient in the protocol database.  Patients will 
receive BENLYSTA at the discretion of their physician. All treatment decisions are at the 
discretion of the patient and their healthcare provider and are not mandated by study design or 
protocol. All assessments are intended to be performed at the time of clinical encounters, per 
routine care. Patients will be enrolled into 1 of 2 cohorts, those who, at baseline, are receiving 
or initiating BENLYSTA (BENLYSTA cohort) or are not receiving BENLYSTA (comparison 
cohort). BENLYSTA and comparison cohort patients may be either treatment initiators or 
current users. Treatment initiators are defined as those patients who have initiated 
immunosuppresants and/or BENLYSTA in the last 2 months, while the current users are those 
who have received immunosuppressants and/or BENLYSTA for ≥ 2 months at the time of entry 
into the registry. The study will enroll approximately 3,000 patients, approximately 2,000 in the 
BENLYSTA cohort and 1,000 in the comparison cohort. Enrollment is expected to occur 
primarily in the US, Canada, and Europe. Each patient will be followed for 5 years contributing 
a total of approximately 7,773 patient years in the BENLYSTA cohort and 3,886 patient years 
in the comparison cohort, respectively, assuming a 10% annual patient drop-out rate and not 
accounting for crossover.  
Data will be collected at enrollment and at approximately 6 month intervals for 5 years (60 
months). All patients will be assessed for AESI including serious infections, opportunistic 
infections and other infections of interest, malignancies (including NMSC), selected serious 
psychiatric events and mortality. Organ damage as assessed by SLICC/ACR Damage Index 
(SDI), concomitant SLE medications including steroids, hospitalizations, demography (eg, age, 
gender, race/ethnicity, where allowed by local regulation), smoking history, alcohol use, and 
SLE disease activity (as assessed by the SLEDAI 2000) will also be evaluated in all patients at 
defined visits (see Table 6-1). Adverse events not collected in this study should be reported in 
accordance with the laws and regulations for marketed products in the country in which the 
event occurred. 
Patients who become pregnant during their participation in this registry will be encouraged to 
also participate in a separate pregnancy registry (if available at the time). 
3 
Objectives 
Primary Objective: 
To evaluate the incidence of the following adverse events of special interest (AESI) over 5 years 
in adults with active autoantibody-positive systemic lupus erythematosus (SLE) who are treated 
with or without BENLYSTA: 

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• Malignancies (excluding non-melanoma skin cancers) 
• Mortality 
• Opportunistic infections and other infections of interest (Appendix 1) 
• Non-melanoma skin cancers (NMSC)  
• Selected serious psychiatric events (Appendix 2) 
• Serious infections 
 
Other Objectives: 
To evaluate the following effectiveness measures in adults with active autoantibody-positive 
SLE who are treated with or without BENLYSTA: 
• Organ damage as assessed by SLICC/ACR Damage Index (Appendix 5) 
• Concomitant SLE medications including steroids 
• Hospitalizations 
 
4 
Outcome Definitions and Measures 
The following outcomes will be collected in the registry: 
Safety 
• Malignancies (excluding NMSCs): Malignancies are cancers (excluding NMSC) that have 
the ability to spread to other parts of the body (metastasize) or to invade and destroy 
tissues and cause death.  
• Mortality: Survival status will be collected at each data collection time point after 
enrollment. If death occurs, the cause of death will be collected.  
• Opportunistic infections and other infections of interest: Opportunistic infections are a 
subset of infections that are caused by organisms that usually do not cause disease in 
immunocompetent individuals but which may cause illness, or more severe illness, when 
the immune system is suppressed. Since there are no general guidelines for labeling 
pathogens as opportunistic without considering the host's immune condition, identification 
of opportunistic infections in this study is based on a list of pathogens which, when 
present, may indicate immune suppression in a patient. These pathogens and infections in 
general are not observed in immunocompetent individuals and will be considered 
opportunistic. Pathogens and infections considered to be opportunistic include but not 
limited to those listed in Appendix 1. All potential opportunistic infections (and other 
infections of interest as noted in Appendix 1), irrespective of seriousness, will be 
collected.  
• Non-melanoma skin cancer: NMSC is a malignant growth of the external surface or 
epithelial layer of the skin. NMSC most often originates from the external skin surface as 
a squamous cell carcinoma or a basal cell carcinoma.  

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• Selected serious psychiatric events: Selected serious psychiatric events suggestive of 
mood disorders and anxiety, as defined in Appendix 2, will be collected. 
• Serious infections: Serious infections, including serious opportunistic infections, are 
defined as those that result in death, are life-threatening; require inpatient hospitalization 
or prolongation of existing hospitalization; require treatment with intravenous 
antimicrobials (eg, antibiotics, antifungals, antivirals); result in persistent or significant 
disability/incapacity; or are, based upon appropriate medical judgment, important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed above. All serious infections will be collected. See Section 7.1 for the 
definition of serious adverse events (SAEs). 
 
Effectiveness 
• Organ damage: The SDI (Appendix 5) is designed to capture items of irreversible organ 
damage present for at least 6 months (Gladman et al, 1996) occurring in patients with SLE 
regardless of exact cause. It consists of 12 organ system scales each having subscales 
comprised of up to 6 components. 
• Concomitant SLE medications including steroids: The medications used to treat SLE 
(eg, immunosuppressants, anti-malarials, corticosteroids, biologics, and investigational 
agents for SLE) will be collected. 
• Hospitalization: An inpatient hospitalization is defined as an admission for greater than 
24 hours. An admission for administration of medication or for routine or planned clinical 
procedures should not be considered a hospitalization. Dates of hospital admission and 
discharge, and whether the hospitalization was SLE-related will be collected, as available. 
 
5 
Inclusion and Exclusion Criteria 
5.1 
Inclusion Criteria 
Patients enrolled in the registry must meet the following inclusion criteria: 
1. Males or females age 18 or older. 
2. Have a clinical diagnosis of active SLE.  
3. Current or history of autoantibody-positive SLE. 
4. Must be treated with SLE therapy including BENLYSTA and/or immunosuppressants 
(eg, azathioprine, methotrexate, cyclophosphamide, mycophenolate, and biologics). 
5. Have the ability to understand the requirements of the study, provide written informed 
consent, including consent for the use and disclosure of research-related health 
information, and comply with the study data collection procedures. 
 

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5.2 
Exclusion Criteria 
Patients will be excluded from participating in the registry if they meet any of the following 
exclusion criteria: 
1. Treatment with an investigational drug within one year of enrollment. Investigational drug 
applies to any drug not approved for sale in the country it is being used. 
2. Currently enrolled in a placebo-controlled BENLYSTA (belimumab) clinical trial or a 
continuation protocol where belimumab is used as an investigational agent. 
3. Patients who have a history of BENLYSTA exposure, but are not currently receiving 
BENLYSTA. 
4. Patients only receiving an anti-malarial for SLE.  
5. Patients only receiving steroids for SLE. 
 
6 
Data Collection 
6.1 
Study Enrollment Evaluations 
The following data will be collected at enrollment (baseline). Data collection for enrollment 
may be carried out over more than one clinical evaluation visit. 
1. Written informed consent (including consent for the use and disclosure of research-related 
health information). 
2. Demographics (eg, age, gender, race/ethnicity (where allowed by local regulation), smoking 
history, alcohol use) 
3. Medical history (including SLE history). Note: To collect additional important information 
on potential suicidality-related events, should any of the psychiatric events marked with an 
asterisk in Appendix 2 be present at enrollment, the investigator should complete the 
Possible Suicidality-Related History Questionnaire (PSRHQ) eCRF (see Appendix 3). 
4. Potential Confounders for Malignancies and/or Infections List (refer to Appendix 7). 
5. Obtain historical and current SLE medications (immunosuppressants, antimalarials, 
corticosteroids and biologics). The name of the each SLE medication and start and stop 
dates will be recorded. In addition, for corticosteroids, the prescribed dose will be recorded. 
If the patient is receiving BENLYSTA, the date of first dose, and route of administration 
(IV or SC) will be recorded as well as name of the other SLE medications the patient was 
receiving at the time BENLYSTA therapy was initiated. 
6. SLEDAI 2000 (see Appendix 6). To complete SLEDAI 2000, data from the following 
laboratory tests if available: Hematology (WBC, platelets), complement (C3, C4), 
anti-dsDNA, routine urinalysis, and spot urine for macroscopic/microscopic/proteinuria 
assessments. Note: Laboratory values should not be attributed on the SLEDAI 2000 unless 
laboratory values were obtained within 30 days of enrollment otherwise the laboratory 
values will be noted as not done.  
7. SLICC/ACR Damage Index (Appendix 5). 
8. Hospitalizations occurring in the previous 6 months. 

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9. Confirm patient meets study eligibility criteria. 
 
6.2 
On Study Evaluations 
After enrollment, patients will continue to be followed regardless of changes in medication until 
study completion. The investigator will manage the patient in accordance with their medical 
judgment and standard of care. Data will be collected on patients approximately every 6 months 
as outlined in the study calendar (Table 6-1). Each evaluation may be conducted within 2 
months (±2 months) of the scheduled data collection time point, except the last time point 
(Month 60), where data collection can occur up to +3 months. 
The following data will be collected at each 6-month time point: 
• SLICC/ACR Damage Index (Appendix 5). 
• SLE medications (eg, immunosuppressants, BENLYSTA, antimalarials, corticosteroids, 
biologics, investigational agents for SLE). The name of each SLE medication and start and 
stop dates will be recorded. If a patient currently using BENLYSTA changes formulation, 
the original BENLYSTA record must be updated with a stop date and a new BENLYSTA 
record needs to be created with a start date for the new formulation.  The new BENLYSTA 
record should also include formulation (IV or SC). 
• In addition, the average daily dose of corticosteroids, in prednisone equivalents, will be 
recorded. 
• Hospitalizations. Dates of inpatient hospital admission and discharge, and whether the 
hospitalization was SLE-related will be collected, as available. 
• Adverse events of special interest (see Section 7.2.1). Note: In order to collect additional 
important information on potential suicidality-related events, should any of the events 
marked with an asterisk in Appendix 2 occur, the investigator will be requested to complete 
the Possible Suicidality-Related History Questionnaire (PSRHQ) eCRF (only the first time 
a serious suicidality-related event is reported and a Possible Suicidality-Related 
Questionnaire (PSRQ) eCRF (each time a serious suicidality-related event is reported). The 
PSRHQ and PSRQ are provided in Appendix 3 and Appendix 4, respectively. 
 
6.3 
Registry Completion 
All patients who do not discontinue, or are not withdrawn, or are not lost to follow-up (see 
Section 6.4) will remain in the registry for 5 years. Record retention should occur in accordance 
with Section 11.6.  
6.4 
Discontinuation and Lost to Follow-Up 
Patients will be free to withdraw from this registry at any time, for any reason. It is understood 
that an excessive rate of withdrawals can render the data un-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided. Patients will continue to be followed 
regardless of changes in medication until study completion. Patients may be withdrawn from 
this registry for any of the following reasons: 

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• Withdrawal of consent  
• Lost to follow-up 
• At the discretion of the investigator 
• Patient enrolls in an interventional trial utilizing an investigational drug or a drug with the 
same mechanism of action as BENLYSTA 
o Note: patients who wish to enroll in an interventional trial with a marketed drug 
being utilized as an investigational agent for the treatment of SLE may be able to 
continue in SABLE following discussion with the GSK medical monitor. 
 
If a patient wishes to discontinue participation in the registry, the data collection for the next 
study evaluation will be obtained at the time of the patient’s next routinely scheduled clinical 
assessment. If data collection has been performed within 2 months before the discontinuation 
visit, it need not be repeated.  
Patients will be considered lost-to-follow-up if no contact can be established by the time a 
patient is beyond 5 years and 3 months from their enrolment date (Day 0). Investigators or 
qualified designees should document attempts to re-establish contact with patients throughout 
the study period. If contact with a patient is re-established before the last follow-up timepoint 
at 60 months (-2/+3 months), follow-up should resume according to the protocol. 

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Table 6-1  
Study calendar 
Time Points 
Data Collection 7 
Enrollment1 
(Day 0) 
6 months  
(± 2 months) 
12 months 
(± 2 months) 
18 months 
(± 2 months) 
24 months 
(± 2 months) 
30 months 
(± 2 months) 
36 months 
(± 2 months) 
42 months 
(± 2 months) 
48 months 
(± 2 months) 
54 months 
(± 2 months) 
60 months 
(-2 / +3 
months) 6 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical History (including SLE history)/  
General Medical Status 
x 
 
 
 
x3 
 
 
 
x3 
 
 
Potential Confounders for Malignancies and/or Infections 
List 
x 
 
 
 
 
 
 
 
 
 
 
Historical SLE Medications 
x 
 
 
 
 
 
 
 
 
 
 
SLEDAI 20002 
x 
 
 
 
 
 
 
 
 
 
 
Verify Eligibility Criteria 
x 
 
 
 
 
 
 
 
 
 
 
SLICC/ACR Damage Index 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Record Current SLE Medications (including 
corticosteroids)4 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Record Hospitalizations 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
Record AEs of Special Interest5 
 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
 
1 
Data collection for enrollment may occur over more than one day.  
2 
Laboratory values should not be attributed on the SLEDAI 2000 unless laboratory values were obtained within 30 days of the assessment. 
3 
Only General Medical Status (current status of medical condition and/or medical procedure/surgery since last reported) is collected at 24 and 48 months. 
4 
SLE Medications include immunosuppressants, biologics, antimalarials, corticosteroids, and investigational agents for SLE. If a patient currently using BENLYSTA 
changes formulation, the original BENLYSTA record must be updated with a stop date and a new BENLYSTA record needs to be created with a start date for the 
new formulation.  The new BENLYSTA record should also include formulation (IV or SC). 
5 
AEs of special interest for this study include mortality, serious infections, opportunistic infections and other infections of interest, selected serious psychiatric events, 
and malignancies (including NMSC). In order to collect additional important information on potential suicidality-related events, should any of the events marked with 
an asterisk in Appendix 2 occur, the investigator will be requested to complete the PSRHQ eCRF (only the first time a serious suicidality-related event is reported) 
and a PSRQ eCRF (each time a serious suicidality-related event is reported). The PSRHQ and PSRQ are provided in Appendix 3 and Appendix 4, respectively. 
6 
For the last time point (60 months), data collection is extended by an additional 1 month and therefore can occur up to 63 months after enrollment (Day 0). This is to 
provide sites with additional time to contact patients before declaring them as lost-to-follow-up. 

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7 
The data collection time intervals of 6 months 2 months are intended to align with routine standard of care visits for SLE patients. With the exception of the last time 
point at 60 months (for which data collection can only be extended up to 63 months), data collection occurring outside the time window (2 months) should be 
assigned to the closest time point. 

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7 
Adverse Events 
7.1 
Definitions 
ADVERSE EVENT (EXPERIENCE): Any unfavorable or unintended sign, symptom, or 
disease that is temporally associated with the use of a study agent but is not necessarily caused 
by the study agent. This includes worsening (eg, increase in frequency or severity) of 
pre-existing conditions. 
SERIOUS ADVERSE EVENT – an adverse event resulting in any of the following outcomes: 
• death 
• is life threatening (ie, an immediate threat to life) 
• inpatient hospitalization* 
• prolongation of an existing hospitalization 
• persistent or significant disability / incapacity 
• congenital anomaly / birth defect 
• is medically important+ 
 
*An inpatient hospitalization is defined as an admission and inpatient stay for at least 24 hours. 
A hospitalization for administration of medication, for routine or planned clinical procedures, 
or for “social” reasons (not the result of any adverse change in the subject’s condition) should 
not be considered an adverse event and should not be reported as a serious adverse event.  
+Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or result in hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed above. These should also 
usually be considered serious. (ICH guidelines, March 1995) 
UNEXPECTED ADVERSE EVENT: An adverse event, the nature or severity of which is not 
consistent with the applicable product information (eg, package insert/summary of product 
characteristics for an approved product). Expected means the event has previously been 
observed and is identified and/or described in the applicable product information. It does not 
mean that the event is expected with the underlying disease(s) or concomitant medications. 
7.2 
Reporting Adverse Events 
7.2.1 Adverse Events of Special Interest 
The following adverse events of special interest (AESI) will be collected in this registry: 
• Malignancies (excluding non-melanoma skin cancers) 
• Mortality 
• Opportunistic infections and other infections of interest (Appendix 1) 

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• Non-melanoma skin cancers (NMSC)  
• Selected serious psychiatric events (Appendix 2) 
• Serious infections 
All AESI identified from enrollment throughout the duration of the study will be recorded on 
the Adverse Event Case Report Form (AE eCRF). All data fields on the AE eCRF should be 
completed.  
7.2.2 Serious AESI and Deaths 
All AESI that meet the criteria of a serious adverse event and deaths must be recorded in the 
SAE section of the protocol database within 24 hours of site personnel becoming aware of a 
SAE. In the event the protocol database cannot be accessed, the SAE Worksheet should be used 
and information faxed to the Drug Safety Designee. All pages of the SAE Database/Worksheet 
should be completed and not held until all information is available. Additional information and 
corrections should be added to the protocol Database/Worksheet when available. 
7.2.3 Other Adverse Events 
Other adverse events (including serious adverse events) not collected as AESIs in this registry 
should be reported in accordance with the laws and regulations for marketed products in the 
country where the event occurred. 
7.3 
Suicidality 
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation (Bachen, 
2009; Timonen, 2003; Stenager, 1992). In order to collect additional important information on 
potential suicidality-related events, should any of the events marked with an asterisk in 
Appendix 2 occur, the investigator will be requested to complete the Possible Suicidality 
Related-History Questionnaire (PSRHQ) eCRF (only the first time a serious suicidality-related 
event is reported) and a Possible Suicidality-Related Questionnaire (PSRQ) eCRF (each time a 
serious suicidality-related event is reported). The PSRHQ collects past medical history in 
relation to SLE-related neuropsychiatric events prior to study enrollment. The PSRQ collects 
other information important for evaluating suicidality-related events such as use of illicit drugs, 
alcohol, other stressors, family history of suicidality and other psychiatric disorders. The 
PSRHQ and PSRQ are provided in Appendix 3 and Appendix 4, respectively. 

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7.4 
Investigator Evaluation of Adverse Events 
The Investigator will evaluate all AESI with respect to seriousness (criteria listed in 
Section 7.1), severity (intensity or grade) and causality (relationship to medicinal product) 
according to the following guidelines: 
SEVERITY: 
• 
Mild 
- causing no limitation of usual activities. 
• 
Moderate  
- causing some limitation of usual activities. 
• 
Severe 
- causing inability to carry out usual activities. 
• 
Life-threatening* 
- potentially life-threatening or disabling; significant 
    medical intervention is required. 
*Note – a severity assessment of life-threatening is not necessarily the same as the seriousness 
criterion of life-threatening. (See “Serious” in Section 7.1). The former means that the event is 
a potential threat to life. The latter means that the event is an immediate threat to life. 
CAUSALITY 
Definitely Related 
- reasonable temporal relationship to medicinal product administration 
- follows a known response pattern (eg, medicinal product is known to 
cause this AE) 
- there is no alternative etiology 
 
Probably Related 
- reasonable temporal relationship 
- follows a suspected response pattern (eg, based on similar drugs) 
- no evidence for a more likely alternative etiology  
 
Possibly Related 
- reasonable temporal relationship 
 
 
 
- little evidence for a more likely alternative etiology 
 
Probably Not Related - does not have a reasonable temporal relationship OR 
 
 
 
- good evidence for a more likely alternative etiology 
 
Not Related 
 
- does not have a temporal relationship OR 
- definitely due to alternative etiology  
 
The causality assessment must be made by the investigator based on information available at 
the time that the AE eCRF or SAE worksheet is completed. The initial causality assessment 
may be revised as new information becomes available.  

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7.5 
Follow-Up of Adverse Events of Special Interest 
AESI (Section 7.2.1) and Serious AESI (Section 7.2.2) that occur from study entry are followed 
until the final outcome is known or until the end of patient participation.  
7.6 
Reporting Serious Adverse Events to the Regulatory Authorities 
and Institutional Review Board/Ethics Committee 
The Sponsor or its designee, will follow all applicable local and national regulatory 
requirements regarding safety reporting. Each investigator must also comply with the applicable 
regulatory requirements related to the reporting of serious AESI to the IRBs/IECs responsible 
for reviewing the study at their site, as well as the regulatory authority(ies) (if applicable).  
AESI that are study endpoints (as defined in Section 7.2.1) generally will not be submitted as 
expedited reports to regulatory authorities or participating investigators. However, serious 
AESIs related to belimumab will be reported by GSK to regulatory authorities as expedited 
individual case safety reports (ICSRs). 
8 
Data Analysis 
8.1 
General Statistical Considerations 
This registry will observe mortality and AESI as well as effectiveness outcomes on patients 
with diverse treatment experience both during the registry and prior to enrollment. Some 
patients may enter the study already receiving BENLYSTA therapy (current user) and some 
patients may initiate BENLYSTA therapy within the last 2 months prior to study entry 
(treatment initiator). During the study, some patients receiving BENLYSTA therapy may stop 
and potentially restart therapy, and some comparison cohort patients may elect to initiate 
BENLYSTA therapy at some point subsequent to enrollment. Because of these complexities, a 
variety of analyses will be employed, some of which consider time periods of switching on and 
off BENLYSTA treatment. Since the initiation of this registry, a SC formulation of belimumab 
has been submitted for marketing authorization.  The protocol database has been modified to 
capture formulation of BENLYSTA but reporting and analyses will not be separated by 
formulation. 
Patients will be considered evaluable in the BENLYSTA cohort upon receiving a single, full or 
partial dose administration of BENLYSTA and collection of enrollment data (Section 6.1) and 
at least 1 post baseline assessment (Section 6.2). Patients will be considered evaluable in the 
comparison cohort if there is collection of enrollment data (Section 6.1) and at least 1 post 
baseline assessment (Section 6.2). 
8.2 
Sample Size Consideration 
This registry will enroll approximately 3,000 patients approximately 2,000 receiving or 
initiating BENLYSTA plus standard of care (BENLYSTA cohort) and 1,000 standard of care 
only (comparison cohort). Each patient will be followed for 5 years, contributing a total of 
approximately 7,773 patient years in the BENLYSTA cohort and 3,886 patient years in the 

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comparison cohort, respectively, assuming a 10% annual patient drop-out rate and not 
accounting for crossover.  
The registry will allow the difference in mortality rate in the BENLYSTA cohort and 
comparison cohort to be established with a 95% CI of +/-0.30 per 100-subject years, based on 
an estimated mortality rate of 0.68 per 100-subject years in both treatment groups (Table 8-1). 
The estimated mortality rate was based on the mortality rate in the pooled IV primary safety 
database in SLE subjects derived from 3 randomized, double-blind, IV placebo-controlled trials, 
referred to as IV SLE CRD studies (ie, integrated database of LBSL02 [placebo-controlled 
treatment phase only], HGS1006-C1056, and HGS1006-C1057) for all subjects (IV belimumab 
and placebo) adjusted for subject years. The precision of the rates of the AESI are provided in 
the table below: 
Table 8-1  
Precision of differences in AE rates estimated from a total of 7773 
patient years in the BENLYSTA cohort and 3886 patient years in the 
comparison cohort, respectively 
Adverse Events 
Reference Rate1 
(per 100-patient years) 
95% Confidence Interval for difference 
in AE rates2 (per 100-patient years) 
All Deaths 
0.68 
±0.32 
Serious infection 
5.80  
±0.93  
Opportunistic infection 
0.136  
±0.14 
Malignancy excl. NMSC 
0.226 
±0.19  
NMSC 
0.226 
±0.19 
Serious Psychiatric Events 
0.410 
±0.25 
1 
The reference AE rates were based on the AE rates in the pooled IV primary safety database derived 
from 3 IV SLE CRD studies (LBSL02, HGS1006-C1056, HGS1006-C1057) and adjusted for subject 
years.  
2 
Assuming that the AE rates in BENLYSTA and the control groups were the same as the reference rate. 
 
 
8.3 
Endpoints and Analysis 
8.3.1 Primary Endpoints 
The primary endpoints are the incidence of the following AESI: 
• Malignancies (excluding NMSC) 
• Mortality 
• Opportunistic infections and other infections of interest (Appendix 1) 
• NMSC 
• Serious psychiatric events (Appendix 2) 
• Serious infections 
 

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8.3.2 Analysis of Primary Endpoints 
In addition to analyses that consider initial treatment group (BENLYSTA cohort vs. comparison 
cohort), analyses that specifically account for changes in therapy (in either group) by 
considering a variety of risk windows will be employed. These analyses will attribute events to 
BENLYSTA treatment if they occur within the designated risk windows for BENLYSTA 
exposure and to comparison treatment otherwise. These analyses will allow for a registry patient 
to contribute person-time to both BENLYSTA treatment, and comparison treatment and as a 
result, will specifically account for treatment switching to BENLYSTA or from BENLYSTA. 
Switching between BENLYSTA and comparison treatment will be taken into account in a 
number of ways in the analysis and will be further defined within the statistical analysis plan. 
No new analyses for changing between BENLYSTA formulation or stratifying by BENLYSTA 
formulation are planned.  Planned analyses are outlined below; all analyses will be detailed in 
the statistical analysis plan. 
• Analysis by initial treatment group of rate per person years of observation time. 
• Analysis by initial treatment group of rate per person years of exposure where 
BENLYSTA exposure ends 14 weeks (approximately 5 half-lives) after cessation of 
treatment. 
• For serious psychiatric events, BENLYSTA exposure is all time on treatment with 
BENLYSTA ending 14 weeks (approximately 5 half-lives) after cessation of treatment, 
with all remaining treatment time attributed to the comparison cohort.  
• For serious infections, opportunistic infections and other infections of interest, 
BENLYSTA exposure is all time on treatment with BENLYSTA ending 6 months after 
cessation of treatment, with all remaining treatment time attributed to the comparison 
cohort. 
• For NMSC and malignancies excluding NMSC, analysis will be performed where all 
events will be attributed to BENLYSTA if the patient was ever exposed to BENLYSTA 
treatment prior to the event and attributed to the comparison cohort otherwise (ie, once 
exposed, always at risk). 
• Mortality will be analyzed applying all the above-mentioned risk windows (eg, 14 weeks,  
6 months, and ever-exposed).  
• Other risk windows (including risk windows for comparison treatment) may also be 
assessed and defined in the statistical analysis plan. 
 
Additional safety analysis will be performed comparing BENLYSTA treatment initiators with 
patients from the comparison cohort that start or switch an immunosuppressant and that have 
comparable background medication and treatment history. Subgroup analysis will be performed 
that will include but not be limited to analysis of patients with positive anti-dsDNA and low 
complement at baseline, patients with SLEDAI 2000 score at baseline (< 10 vs ≥ 10), SDI (0 vs 
≥ 1), steroid use (yes vs no; ≤ 7.5 mg/day vs > 7.5 mg/day), immunosuppressant use (yes vs no; 
mycophenolate vs immunosuppressant other than mycophenolate), region (US/Canada vs 
Europe vs other), and race (black race vs other). Safety analyses will be adjusted for potential 
confounding factors (Appendix 7) through propensity score methods or other appropriate 
statistical methods. No new analyses for changing between BENLYSTA formulation or 

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stratifying by BENLYSTA formulation are planned.  Further details of the safety analyses will 
be described in the statistical analysis plan. 
8.3.3 Effectiveness Endpoints and Analysis 
Additional endpoints include the following: 
• Organ damage as assessed by SLICC/ACR Damage Index (Appendix 5) 
• Concomitant SLE medications including steroids 
• Hospitalizations 
 
For any effectiveness endpoint analyses performed, methods to reduce the potential impact of 
confounding may be employed. These methods could include subgroup analysis, modeling 
adjusting for baseline and/or other confounding variables, or patient matching techniques like 
propensity score analysis. Furthermore, analyses considering changes in BENLYSTA use over 
time (eg, on or off treatment, but not changes between BENLYSTA formulations) in order to 
assess BENLYSTA effectiveness, as well as evaluate how these endpoints vary in response to 
BENLYSTA treatment will be assessed and further explored as appropriate. These analyses 
will be described in the statistical analysis plan.  
9 
Scientific Advisory Committee (SAC) 
A Scientific Advisory Committee (SAC) consisting of global clinical experts, along with GSK 
staff (clinical, statistics, epidemiology) will be formed. The SAC will meet as needed to review 
the data collected. 
10 
Study Limitations 
This is a registry and, as such, participants are not randomized into study arms. Due to the lack 
of randomization, there is a significant risk of confounding (ie, imbalance in important baseline 
characteristics between the BENLYSTA cohort and the comparison cohort where these 
characteristics are also risk factors for the outcomes). The present study attempts to minimize 
such confounding by selecting comparison patients that are as similar as possible to 
BENLYSTA cohort and will also attempt to account for confounding by further adjustment in 
the analysis using relevant statistical methods (such as propensity score matching or adjustment 
for baseline factors) (see Section 6.2). However, as with all non-randomized observational 
studies, residual unmeasured confounding may still exist. In addition, although the study is 
designed to specifically attempt to enroll a sample of SLE patients who are closely matched in 
both cohorts, it may be that the final enrolled study sample is not as well matched as desired 
due to multiple patient factors that can't be controlled for. The Sponsor will monitor enrollment 
for the proportion of patients who are treatment initiators versus current users and communicate 
to the sites the interest to achieve a reasonable balance for both groups.  
Patients receiving commercially available belimumab may be seen more often by their medical 
care providers as compared to the bi-annual visits of standard of care patients. This may create 

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a reporting bias with increased reporting of events for some outcomes in the BENLYSTA 
group. 
11 
Study Administration 
This study is sponsored by GlaxoSmithKline (GSK) LLC. They will lead on the operational 
conduct of this observational study world-wide working with contract research organizations. 
11.1 Informed Consent 
The consent form must be approved by the Institutional Review Board (IRB) or Institutional 
Ethics Committee (IEC) and contain all elements required by national, state, local, and 
institutional regulations or requirements. In the event that local regulations/laws require a 
Privacy Authorization this will be included as part of the informed consent process. Informed 
consent will be obtained by investigators for each patient whose data are included in this study. 
A copy of the signed informed consent must be given to each study patient. 
11.2 Institutional Review Board Review/Independent Ethics Committee 
Review and Approval 
Regulatory approval or notification will be obtained or performed, respectively, in countries 
where this is required. IRB/IEC approval will be obtained by participating investigators or a 
representative thereof; however, application will be made to central IRBs/IECs governing 
regions or countries wherever this is feasible. 
11.3 Protocol Revisions 
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design or affects statements in the 
informed consent form, the informed consent form must be revised accordingly and submitted 
to the IRB/IEC for review and approval. The approved consent form must be used to obtain 
informed consent from new patients prior to enrollment and must be used to obtain informed 
consent from patients already enrolled if they are affected by the amendment. 
11.4 Data Management 
The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each patient. The investigator is also responsible for maintaining any source documentation 
related to the study, including any films, tracings, computer discs, or tapes.  
The anonymity of participating patients must be maintained. For data collection and 
management purposes, patients are to be identified by a patient number only. Documents that 
identify the patient beyond patient number will not be submitted to the sponsor (eg, the signed 
informed consent document; patient initials) and must be maintained in strict confidence by the 

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investigator, except to the extent necessary to allow auditing by the regulatory authorities, study 
monitor, or sponsor representatives. 
Site personnel record all data for each study patient through electronic case report forms 
(eCRFs) using an Electronic Data Capture (EDC) system provided and approved by the sponsor. 
Sites must complete the eCRFs in a timely manner and the investigator must promptly review 
the completed eCRFs for each patient. As the person ultimately responsible for the accuracy of 
all eCRF data, the investigator must sign the Investigator's Statement in each patient's eCRF. 
The EDC system automatically generates queries resulting from the computer checks embedded 
into the system, so as to ensure accuracy, quality, consistency, and completeness of the 
database. Manual queries resulting from review by monitors, medical coders, and other Data 
Management staff are also generated from within the EDC system, where they are tracked. Sites 
resolve the queries and correct the entered data when necessary. Every change to data is 
captured in the EDC system audit trail. Upon completion of the study, or after reaching a pre-
specified point in the study, Data Management will lock the database and generate the SAS 
datasets necessary for data analysis and reporting. Upon completion of the study, each site will 
be provided with the eCRFs for each of their patients. 
11.5 Study Conduct 
The study sponsor or designee will monitor the conduct of the study. The sponsor may review 
eCRFs and compare them with source documents to verify accurate and complete collection of 
data and confirm that the study is being conducted according to the protocol. Monitors or 
auditors representing the sponsor may also similarly evaluate the study. For these purposes, the 
investigator will make eCRFs and source documents available when requested.  
In addition, the study may be evaluated by representatives of the national regulatory authorities, 
who will also be allowed access to study documents. The investigators should promptly notify 
GlaxoSmithKline of any audits they have scheduled with any regulatory authority. 
11.6 Retention of Records 
The investigator shall retain all records and source documents pertaining to the study, including 
any films, tracings, computer discs, or tapes. They will be retained for the longer of the 
maximum period required by the country and institution in which the study is conducted, or the 
period specified by the sponsor at the time the study is completed, terminated, or discontinued. 
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor. 
11.7 Publication Policy 
Reports to regulatory authorities will be provided as appropriate and agreed with the relevant 
authorities. 

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This study is a multi-center observational research study. Data from all sites participating in the 
multi-center observational initiative will be pooled and analyzed. The investigators 
acknowledge that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and the sponsor’s representatives. Neither the 
participating institutions nor the principal investigators shall publish or present the results of 
the study prior to the publication of the multi-center study publication. The investigators agree 
that the sponsor will be the coordinator and arbitrator of all multi-center study publications. For 
multi-center studies, no investigator will be authorized to publish study results from an 
individual center until the earlier of the multi-center study results are published or 12 months 
after the end or termination of the multi-center study at all sites. 
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and comment 
at least 60 days prior to its submission for publication or presentation. No publication or 
presentation with respect to the study shall be made unless and until all of the sponsor’s 
comments on the proposed publication or presentation have been considered and any 
information determined by the sponsor to be confidential information has been removed. If 
requested in writing by the sponsor, the investigator shall withhold material from submission 
for publication or presentation for an additional 60 days to allow for the filing of a patent 
application or the taking of other measures to establish and preserve the sponsor’s proprietary 
rights. 
11.8 Study or Study Site Termination 
If the sponsor, the investigator, IRB/IEC, or a regulatory authority discovers conditions arising 
during the study that indicate that the study should be halted or that the study center should be 
terminated, this action may be taken after appropriate consultation between the sponsor and the 
investigator. Conditions that may warrant termination of the study include, but are not limited 
to, the following: 
• Sufficient information has accumulated to meet the primary scientific objectives of the 
observational study. 
• Other methods of gathering appropriate information become achievable or are deemed 
preferable. 
• The feasibility of collecting sufficient information diminishes to unacceptable levels 
because of low exposure rates, poor enrollment, or losses to follow-up. 
 
The study site may warrant termination under the following conditions: 
• Failure of the investigator to enroll patients into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory authority regulations. 
• Submission of knowingly false information from the research facility to GSK, study 
monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 

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List of Appendices 
Appendix 1 
Opportunistic Infections and Other Infections of Interest ............................ 45 
Appendix 2 
Serious Psychiatric Events ............................................................................ 46 
Appendix 3 
Possible Suicidality-Related History Questionnaire (PSRHQ) .................... 48 
Appendix 4 
Possible Suicidality-Related Questionnaire (PSRQ) .................................... 49 
Appendix 5 
SLICC/ACR Damage Index (SDI) ............................................................... 50 
Appendix 6 
SLEDAI 2000 ............................................................................................... 52 
Appendix 7 
Potential Confounders  for Malignancies and/or Infections List .................. 53 
 

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Appendix 1 
Opportunistic Infections and Other Infections of 
Interest 
 
Opportunistic infections and other infections of interest are a subset of infections that are caused by 
organisms that usually do not cause disease in immunocompetent individuals but which may cause 
illness, or more severe illness, when the immune system is suppressed. Since there are no general 
guidelines for labeling pathogens as opportunistic without considering the host's immune condition, 
identification of opportunistic infections and other infections of interest in this study is based on the 
following list of pathogens which when present may indicate immune suppression in a patient. 
Pathogens considered to cause opportunistic infections and other infections of interest include but are 
not limited to the following: 
Acinetobacter infection 
Aspergillosis 
Blastomycosis, extrapulmonary 
Candidiasis of esophagus, bronchi, trachea, or lungs 
Coccidiomycosis, dissemintaed or extrapulmonary 
Cryptococcosis, extrapulmonary 
Cryptosporidiosis infection, chronic intestinal (> 1 month duration) 
Cytomegalovirus disease (other than liver, spleen, or nodes) 
Herpes simplex bronchitis, pneumonitis, or esophagitis 
Disseminated herpes zoster or involving at least 2 distinct episodes 
Herpes virus associated Kaposi's sarcoma 
Histoplasmosis disseminated or extrapulmonary 
Human polyomavirus infection  
Isosporiasis, chronic intestinal (> 1 month’s duration) 
Listeriosis 
Mycobacterium avium complex or M. Kansasii, disseminated or extrapulmonary 
Mycobacterium infections, other species or unidentified species, disseminated or extrapulmonary (eg, 
M. haemophilium, M. fortuitum, or M. marinum)  
Nocardiosis 
Polyomavirus (JC virus or BK virus)-associated nephropathy (including progressive multifocal 
leukoencephalopathy) 
Pneumocystis jiroveci infection 
Toxoplasmosis of brain 
Other infections of interest that should be recorded in this registry, but which are not generally 
considered opportunistic, include: 
Mycobacterium tuberculosis, any site, latent or active 
Salmonella sepsis 
Hepatitis B  
Hepatitis C 
All other (ie, non-disseminated or single episode) herpes zoster (shingles) 
 

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Appendix 2 
Serious Psychiatric Events 
 
The following events suggesting serious mood disorders (including suicidality) and anxiety will 
be collected if serious.  
 
Adjustment disorder 
Adjustment disorder with anxiety 
Adjustment disorder with depressed mood 
Adjustment disorder with disturbance of conduct 
Adjustment disorder with mixed anxiety and depressed mood 
Adjustment disorder with mixed disturbance of emotion and conduct 
Affective disorder 
Agitated depression 
Anxiety 
Anxiety disorder 
Anxiety disorder due to a general medical condition  
Bipolar I disorder 
Bipolar II disorder 
Bipolar disorder 
*Completed suicide 
Cyclothymic disorder 
Depressed mood 
Depression 
Depression post-operative 
*Depression suicidal 
Depressive delusion 
Depressive symptom 
Dysthymic disorder 
Generalised anxiety disorder 
*Intentional overdose 
*Intentional self-injury 
Major depression 
Menopausal depression 
Mood disorder due to a general medical condition 
*Multiple drug overdose intentional 
*Poisoning deliberate 
Postpartum depression 
*Self injurious behaviour 
*Self-injurious ideation 
*Suicidal behaviour 
*Suicidal ideation 
*Suicide attempt 
 

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In order to collect additional information on potential suicidality-related events, should any of 
the events indicated with the asterisk occur, the investigator will be requested to complete the 
Possible Suicidality-Related History Questionnaire (PSRHQ, only the first time a serious 
suicidality-related event is reported) and a Possible Suicidality-Related Questionnaire (PSRQ) 
(each time a serious suicidality-related event is reported). The PSRHQ collects past medical 
history in relation to SLE-related neuropsychiatric events prior to study enrollment. The PSRQ 
collects other information important for evaluating suicidality-related events such as use of 
illicit drugs, alcohol, other stressors, family history of suicidality and other psychiatric 
disorders. The PSRHQ and PSRQ are provided in Appendix 3 and Appendix 4, respectively. 
 

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Appendix 3 
Possible Suicidality-Related History Questionnaire 
(PSRHQ) 
Date of Assessment: 
 
                                                              (DDMMMYYYY) 
Has the subject had any SLE-related neuropsychiatric events prior to study start?  ❏ Yes  ❏ No 
 
If Yes, check all that apply and provide the most recent date of occurrence: 
 
Event 
Date 
(DDMMMYYYY) 
❏ 
Acute Confusional State 
❏ 
Acute Inflammatory Demyelinating Polyradiculoneuropathy 
(Guillain-Barré Syndrome) 
❏ 
Anxiety Disorder 
❏ 
Aseptic Meningitis 
❏ 
Autonomic Disorder 
❏ 
Cerebrovascular Disease 
❏ 
Cognitive Dysfunction 
❏ 
Demyelinating Syndrome 
❏ 
Headache 
❏ 
Mononeuropathy Single 
❏ 
Mononeuropathy Multiplex 
❏ 
Mood Disorders 
❏ 
Movement Disorder (Chorea) 
❏ 
Myasthenia Gravis 
❏ 
Myelopathy 
❏ 
Neuropathy, Cranial 
❏ 
Plexopathy 
❏ 
Polyneuropathy 
❏ 
Psychosis 
❏ 
Seizures and Seizure Disorders 

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Appendix 4 
Possible Suicidality-Related Questionnaire (PSRQ) 
 
Is the subject currently using illicit drugs? 
❏ Yes ❏ No 
 
If Yes, check all that apply: 
❏ Amphetamines    ❏ Benzodiazepines    ❏ Cannabinoids    ❏ Cocaine    ❏ Opiates 
❏ Other, Specify:  ______________________________________ 
 
Is the subject currently using alcohol? 
❏ Yes ❏ No 
 
If Yes, Average Unit(s) of Alcohol/Week: 
 
Has the subject experienced any recent stress? 
❏ Yes ❏ No 
 
If Yes, check all that apply: 
❏ Family Problems    ❏ Relationships    ❏ Employment/ Unemployment    ❏ Finances 
❏ Other Factors, Specify:   
 
Any family history of suicidality? 
❏ Yes ❏ No 
 
If Yes, check ideation and/or behavior next to all that apply:  
Father       ❏ Ideation    ❏ Behavior 
Mother     ❏ Ideation    ❏ Behavior 
Sibling     ❏ Ideation    ❏ Behavior 
Other       ❏ Ideation    ❏ Behavior 
 
Any family history of psychiatric disorders? ❏ Yes ❏ No 
 
If Yes, specify disorder next to all that apply:  
 
Father     __________________________________________ 
 
Mother    __________________________________________ 
 
Sibling    __________________________________________ 
 
Other      __________________________________________ 
 

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Appendix 5 
SLICC/ACR Damage Index (SDI) 
 
System Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index for Systemic Lupus Erythematosus 
 
Item  
Score 
Ocular (either eye, by clinical assessment) 
Any cataract ever  
1 
Retinal change or optic atrophy  
1 
 
Neuropsychiatric 
Cognitive impairment (eg memory deficit, difficulty with  
1 
calculation, poor concentration, difficulty in spoken or written 
language, impaired performance levels) or major psychosis 
Seizures requiring therapy for 6 months  
1 
Cerebrovascular accident ever (score 2 > 1)  
1 (2) 
Cranial or peripheral neuropathy (excluding optic)  
1 
Transverse myelitis  
1 
 
Renal 
Estimated or measured glomerular filtration rate < 50%  
1 
Proteinuria > 3.5 gm/24hours  
1 
Or 
End-stage renal disease (regardless of dialysis or transplantation)  
3 
 
Pulmonary 
Pulmonary hypertension (right ventricular prominence, or loud P2)  
1 
Pulmonary fibrosis (physical and radiograph)  
1 
Shrinking lung (radiograph)  
1 
Pleural fibrosis (radiograph)  
1 
Pulmonary infarction (radiograph)  
1 
 
Cardiovascular 
Angina or coronary artery bypass  
1 
Myocardial infarction ever (score 2 if > 1)  
1 (2) 
Cardiomyopathy (ventricular dysfunction) 
1 
Valvular disease (diastolic, murmur, or systolic murmur > 3/6)  
1 
Pericarditis for 6 months, or pericardiectomy  
1 
 
Peripheral vascular 
Claudication for 6 months  
1 
Minor tissue loss (pulp space)  
1 
Significant tissue loss ever (eg loss of digit or limb)(score 2 if > 1 site) 
1 (2) 
Venous thrombosis with swelling, ulceration, or venous stasis  
1 
 
Gastrointestinal 
Infarction or resection of bowel below duodenum, spleen, liver, or  
1 (2) 
gall bladder ever, for cause any (score 2 if > 1 site) 
Mesenteric insufficiency  
1 
Chronic peritonitis  
1 
Stricture or upper gastrointestinal tract surgery ever  
1 

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Musculoskeletal 
Muscle atrophy or weakness  
1 
Deforming or erosive arthritis (including reducible deformities, excluding avascular necrosis) 
1 
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis) 
1 
Avascular necrosis (score 2 if > 1)  
1 (2) 
Osteomyelitis  
1 
 
Skin 
Scarring chronic alopecia  
1 
Extensive scarring or panniculum other than scalp and pulp space  
1 
Skin ulceration (excluding thrombosis) for > 6 months  
1 
 
Premature gonadal failure 
1 
 
Diabetes (regardless of treatment) 
1 
 
Malignancy (exclude dysplasia) (score 2 if > 1 site) 
 1 (2) 
 
(From the Systemic Lupus International Collaborating Clinics (SLICC) and the American College of Rheumatology 
Diagnostic and Therapeutic Criteria Committee, 1996) 
 
Gladman EM, Ginzler E, Goldsmith C et al. SLICC/ACR damage index for SLE. Arthritis Rheum 1996a;39(3):363-9. 
 
 

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Appendix 6 
SLEDAI 2000 
Score if descriptor is present at time of visit or  30 days of enrollment visit. 
 
Weight 
SLEDAI 
Score 
Descriptor 
Definition 
8 
________ 
Seizure 
Recent onset, exclude metabolic, infectious or drug causes. 
8 
________ 
Psychosis 
Altered ability to function in normal activity due to severe disturbance in the 
perception of reality. Include hallucinations, incoherence, marked loose associations, 
impoverished thought content, marked illogical thinking, bizarre, disorganized, or 
catatonic behavior. Excluded uremia and drug causes. 
8 
________ 
Organic brain 
syndrome 
Altered mental function with impaired orientation, memory or other intelligent 
function, with rapid onset fluctuating clinical features. Include clouding of 
consciousness with reduced capacity to focus, and inability to sustain attention to 
environment, plus at least two of the following: perceptual disturbance, incoherent 
speech, insomnia or daytime drowsiness, or increased or decreased psychomotor 
activity. Exclude metabolic, infectious or drug causes. 
8 
________ 
Visual disturbance 
Retinal changes of SLE. Include cytoid bodies, retinal hemorrhages, serious exodate 
or hemorrhages in the choroids, or optic neuritis. Exclude hypertension, infection, or 
drug causes. 
8 
________ 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving cranial nerves. 
8 
________ 
Lupus headache 
Severe persistent headache: may be migrainous, but must be nonresponsive to 
narcotic analgesia. 
8 
________ 
CVA 
New onset of cerebrovascular accident(s). Exclude arteriosclerosis. 
8 
________ 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual, infarction, splinter 
hemorrhages, or biopsy or angiogram proof of vasculitis. 
4 
________ 
Arthritis 
≥ 2 joints with pain and signs of inflammation (i.e. tenderness, swelling, or effusion). 
4 
________ 
Myositis 
Proximal muscle aching/weakness, associated with elevated creatine 
phosphokinase/adolase or electromyogram changes or a biopsy showing myositis. 
4 
________ 
Urinary casts 
Heme-granular or red blood cell casts. 
4 
________ 
Hematuria 
> 5 red blood cells/high power field. Exclude stone, infection or other cause. 
4 
________ 
Proteinuria 
> 0.5 gm/24 hours.  
4 
________ 
Pyuria 
> 5 white blood cells/high power field. Exclude infection. 
2 
________ 
Rash 
Inflammatory type rash. 
2 
________ 
Alopecia 
Abnormal, patchy or diffuse loss of hair. 
2 
________ 
Mucosal ulcers 
Oral or nasal ulcerations. 
2 
________ 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion, or pleural thickening. 
2 
________ 
Pericarditis 
Pericardial pain with at least 1 of the following: rub, effusion, or electrocardiogram or 
echocardiogram confirmation. 
2 
________ 
Low complement 
Decrease in CH50, C3, or C4 below the lower limit of normal for testing laboratory. 
2 
________ 
Increased DNA 
binding 
Increased DNA binding by Farr assay above normal range for testing laboratory. 
1 
________ 
Fever 
> 38°C. Exclude infectious cause. 
1 
________ 
Thrombocytopenia 
< 100,000 platelets/ x109/L, exclude drug causes. 
1 
________ 
Lenkopenia 
< 3,000 White blood cell/ x109/L, exclude drug causes. 
TOTAL 
SLEDAI 
SCORE 
 
________ 
 
 
 
Adapted from:  
Dafna D Gladman, Dominique Ibañez and Murray B Urowitz, Systemic lupus erythematosus disease activity index 2000. J Rheumatol 
2002;29;288-291. 

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Appendix 7 
Potential Confounders  for Malignancies and/or 
Infections List 
 
• Demographic and other general characteristics 
- Age 
- Gender 
- Weight 
- Height 
- Race/ethnicity 
- Smoking history 
- Family history of cancer – first degree relatives & grandparents 
- Alcohol history 
- Female only: 
- Parity 
- Hormonal status 
 
• SLE disease profile 
- Age at diagnosis 
- Organ involvement (SLEDAI 2000 Domains) 
- Disease Severity (SLEDAI 2000) 
- Organ Damage (SDI)  
- ANA status  
- Anti-dsDNA status 
- Quantitative Immunoglobulins (IgG, IgA, IgM) 
- Complement levels (C3/C4) 
- Total white blood cell count 
- Neutrophil differential % 
- Lymphocyte differential % 
 
• SLE treatment  
- Name and duration of current SLE medications: including anti-malarials, biologics, 
steroids, and immunosuppressants at baseline 
- In addition, for steroids add dose 
 
• Co-morbidities 
- ESRD/dialysis 
- Hepatitis B 
- Hepatitis C 
- HIV 
- Sjogren’s Syndrome (Secondary) 
- Neutropenia 
- Post-transplant (any transplant) 
- Diabetes 
- Splenectomy 

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- Chronic lung disease 
- Known immunoglobulin deficiencies  
- Tuberculosis (latent or active) 
- History of cancer (including NMSC) 
- History of serious infection 
 
• Vaccinations 
- BCG 
- Pneumococcal 
- Influenza vaccine 
- Human papillomavirus (HPV)  
- Hepatitis 
- Varicella zoster 
- Any live vaccine received  30 days prior to  enrollment  
 

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