Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches (The ABC Study)
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: Oklahoma Medical Research Foundation

1 
 
 
 
 
 
Clarification of Abatacept Effects in SLE with Integrated Biologic and 
Clinical Approaches (The ABC Study) 
 
 
[BMS PROTOCOL NUMBER: IM101-345 
 
 
 
Joan T. Merrill, M.D. 
Clinical Pharmacology Research Program 
Oklahoma Medical Research Foundation 
825 NE 13th St, MS 22 
Oklahoma City, OK  73104 
 Telephone: 405-271-7805 
Fax: 405-271-8797 
Email: joan-merrill@omrf.org 
 
 
 
 
 
[Protocol Version January 8, 2016] 
 
 
 
 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS ..............................................................................................................2 
PROTOCOL SYNOPSIS...……………………………………………………………………...5 
1 
INTRODUCTION ......................................................................................................9 
1.1 
Pathology of Systemic Lupus (SLE) ..........................................................................10 
1.2 
Relevance of Abatacept mechanism to SLE ...............................................................10 
1.3 
Summary of Results of Investigational Program ........................................................14 
1.3.1 
Pharmacology of Abatacept ........................................................................................14 
1.3.2 
Human Pharmacokinetics of Abatacept ......................................................................15 
1.3.3 
Clinical Safety of IV Abatacept in SLE and SC Form in RA ....................................20 
1.3.3.1 
Drug-Related Adverse Events ....................................................................................29 
1.3.4 
Clinical Efficacy of Abatacept Subcutaneous Formulation ........................................30 
1.4 
Overall Risk/Benefit Assessment ...............................................................................31 
1.5 
Research Hypothesis ...................................................................................................31 
1.6 
Study Rationale ...........................................................................................................32 
2 
STUDY OBJECTIVES ............................................................................................32 
2.1 
Primary Objective .......................................................................................................32 
2.2 
Secondary Objectives .................................................................................................32 
3 
ETHICAL CONSIDERATIONS ............................................................................33 
3.1 
Good Clinical Practice ................................................................................................33 
3.2 
Institutional Review Board/Independent Ethics Committee ......................................33 
3.3 
Informed Consent .......................................................................................................34 
4 
INVESTIGATIONAL PLAN ..................................................................................35 
4.1 
Study Design and Duration .........................................................................................35 
4.2 
Study Population .........................................................................................................37 
4.2.1 
Inclusion Criteria ........................................................................................................37 
4.2.2 
Exclusion Criteria .......................................................................................................38 
4.2.3 
Discontinuation of Subjects from Treatment ..............................................................39 
5 
TREATMENTS ........................................................................................................40 
5.1 
Study Treatment: Abatacept .......................................................................................40 
5.1.1 
Identification ...............................................................................................................40 
5.1.2 
Packaging and Labeling ..............................................................................................40 

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5.1.3 
Handling and Dispensing ............................................................................................40 
5.2 
Drug Ordering and Accountability .............................................................................41 
5.2.1 
Initial Orders ...............................................................................................................41 
5.2.2 
Re-Supply ...................................................................................................................41 
5.3 
Method of Assigning Subjects to a Treatment ...........................................................41 
5.4 
Selection and Timing of Dose for Each Subject .........................................................41 
5.4.1 
Dose Modifications .....................................................................................................41 
5.5 
Blinding/Unblinding ...................................................................................................42 
5.6 
Concomitant Treatments .............................................................................................42 
5.6.1 
Prohibited and/or Restricted Treatments ....................................................................42 
5.6.2 
Other Restrictions and Precautions .............................................................................42 
5.7 
Treatment Compliance ................................................................................................42 
6 
STUDY ASSESSMENTS AND PROCEDURES ...................................................43 
6.1 
Time and Events Schedule ..........................................................................................44 
6.2 
Study Materials ...........................................................................................................45 
6.3 
Safety Assessments .....................................................................................................45 
6.3.1 
Physical Examinations ................................................................................................45 
6.3.2 
Breast and Hematologic Cancer Screening ................................................................45 
6.4 
Efficacy Assessments .................................................................................................45 
6.4.1 
Primary Efficacy Assessment .....................................................................................45 
6.4.2 
Secondary Efficacy Assessments ...............................................................................46 
6.5 
Other Assessments ......................................................................................................47 
7 
ADVERSE EVENT REPORTING .........................................................................53 
7.1 
Adverse Events ...........................................................................................................53 
7.1.1 
Serious Adverse Events ..............................................................................................53 
7.1.2 
Nonserious Adverse Events ........................................................................................54 
7.1.3 
Assignment of Adverse Event Intensity and Relationship to Abatacept ....................54 
7.2 
Collection and Reporting ............................................................................................55 
7.2.1 
Serious Adverse Event Collecting and Reporting ......................................................55 
7.2.2 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting .............................54 
7.3 
Laboratory Test Abnormalities ...................................................................................56 
7.4 
Overdose .....................................................................................................................56 
7.5 
Pregnancy ...................................................................................................................56 

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7.6 
Potential Drug-Induced Liver Injury (DILI) ...............................................................52 
7.7 
Other Safety Considerations ..................................................................................57 
8 
DATA MONITORING COMMITTEE ..................................................................57 
9 
STATISTICAL CONSIDERATIONS ....................................................................58 
9.1 
Sample Size Determination ........................................................................................58 
9.2 
Populations for Analyses ............................................................................................58 
9.3 
Endpoint Definitions ...................................................................................................59 
9.4 
Analyses ......................................................................................................................59 
9.4.1 
Demographics and Baseline Characteristics .............................................................59 
9.4.2 
Safety Analyses ..........................................................................................................59 
9.4.3 
Efficacy Analyses .......................................................................................................59 
9.4.4 
Other Analyses ............................................................................................................60 
10 
STUDY MANAGEMENT........................................................................................60 
10.1 
Compliance with the Protocol ....................................................................................60 
10.1.1 
Compliance with the Protocol and Protocol Revisions ..............................................60 
10.2 
Records Retention .......................................................................................................61 
10.2.1 
Records Retention .......................................................................................................61 
10.2.2 
Study Drug Records ....................................................................................................61 
10.3 
Destruction of Investigational Product .......................................................................61 
11 
GLOSSARY OF TERMS.........................................................................................62 
12 
LIST OF ABBREVIATIONS ..................................................................................63 
13 
REFERENCES .........................................................................................................66 
APPENDIX 1: HYBRID SLEDAI with SSFI, rSFI and PGA…….……………………….70 
APPENDIX 2: BILAG 2004……………………………………………………….………….87 
APPENDIX 3: ANCILLARY STUDY WITH EXAGEN DIAGNOSTICS……….……….110 
APPENDIX 4: ANCILLARY STUDY WITH DR JOSEPH CRAFT………….………….113 
APPENDIX 5: ANCILLARY STUDY WITH DRS KYTTARIS AND TSOKOS.............115 
APPENDIX 6: BMS ANCILLARY STUDIES………………………..……………………117 
APPENDIX 7: REPOSITORY……………………………………………………..………..120 
 

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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Clarification of Abatacept Effects in SLE with Integrated Biologic 
and Clinical Approaches (The ABC Study)The ABC Study:  
Site Numbers/ Names: 
Site 1: Oklahoma Medical Research Foundation 
Research Hypothesis: 
Abatacept is effective in lupus arthritis and this will be discernible 
in a small trial with robust endpoints which incorporates 
withdrawal of background immune suppressants 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
1. Abatacept or placebo will be given in a 1:1 randomization 
subcutaneously q week for six months. Patients may elect 
to continue six more months on open label Abatacept.  
2. Background Immune Suppressants will be withdrawn at 
any time between screening and the first dosing visit.  
3. At or after screening, patients may elect 40-160 mg 
depomedrol shots prn not to exceed 320 mg total up to 
and including the Month 2 Visit (two months after the first 
dosing visit) 
4. Additional steroids or immune suppressants, if necessary, 
will be allowed but the patient will be considered a non-
responder on that basis 
5. At the 3 month visit patients with significant clinical flare 
unresponsive to optional per protocol treatments may elect 
to receive open label Abatacept but will be considered 
non-responders in the primary endpoint at six months. 
Study Objectives: 
• 
Primary: 
• 
Secondary: 
Primary Objective: To compare response rates between 
Abatacept-Treated and Placebo-Treated Patients with active 
lupus arthritis in a trial designed with background immune 
suppressant withdrawal, limited steroid rescue, and a robust, 
discriminatory endpoint. Statistical powering is based on this 
primary objective. The trial design and primary endpoint 
(response by BICLA) have been pre-tested by us for safety and 
ability to ensure placebo group non-response. This will support a 
rational decision about further development of abatacept for SLE 
at minimal cost. 2.) Secondary clinical endpoints will include: 
SRI 4/5, changes in joint counts, SLEDAI, BILAG, CLASI, PGA, 
and LFA simplified instrument measures. PK and immunogenicity 
studies will be performed to help in interpretation of outcomes. 
Novel biologic discovery will be integrated into the clinical trial to 
support both pre-specified and exploratory biomarker discovery. 
Data will be generated that might be used to help select more 
appropriate patient subsets for future trials and, along with PK 
data, help to guide optimal dosing strategies. Optimizing patient 
selection and dosing are important goals for further increasing 
demonstrable effect size in trials by increasing the response rates 

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in the treatment group. 
Study Design: 
This study will be a double blind, randomized, placebo-controlled 
clinical trial with 1:1 randomization of patients to abatacept 125 
mg weekly subcutaneous dose or placebo, with the. withdrawal of 
background immune suppressants. Limited steroid rescue allowed 
per protocol. Additional meds will define non-response the primary 
endpoint date of six months. Flaring patients may elect to receive 
open label abatacept at Month 3 but will also be defined as non-
responders in the primary endpoint. All patients may elect to 
receive open label abatacept for an additional six months after the 
primary endpoint date, with two follow up visits (2 and 4 months 
post withdrawal) to assess withdrawal effects and to complete the 
safety assessment. 
Accrual Goal: 
(Total subjects) 
This study will continue to recruit until we achieve the goal of 60 
patients who complete study visits through the 6 month endpoint. 
Accrual Rate: 
(Number of subjects 
expected per month) 
We expect to enroll 5 patients/month given entry criteria,            
recruitment track record, and patient appeal of protocol  
  (in particular the early crossover to open label treatment)            
FPFV: 
LPFV: 
Follow Up: 
 
• 
FPFV:  October 30 2013 
• 
LPFV: December 31 2015 
• 
Follow Up: April 31 2016 
Correlative Studies: 
(PK/PD, etc.) 
Extensive exploratory protocol-specific and ancillary immune 
pharmacodynamic studies, focusing first on changes in IFN alpha, 
BLyS and other B Cell pathways. A major focus will also be on T 
Cell pathways with a focus on T suppressor/TH17 dichotomy after 
treatment with abatacept. A responder analysis will be performed 
in order to generate hypotheses useful for selecting appropriate 
patients for this treatment and optimizing dosing strategies. 
Inclusion Criteria: 
1) Signed Written Informed Consent 
2) 4 1997 revised ACR Classification Criteria for SLE 
3)  Active polyarticular arthritis meeting at minimum BILAG 
      2004 B definition with a minimum of 3 tender and 3 
      swollen joints observed at the screening visit 
4)   Men and women 18 to 70 years of age.  
5)   Women of childbearing potential and men with partners of 
      childbearing potential must use an acceptable method of 
      birth control throughout the study 
6)   Women of childbearing potential must have a negative 
       urine pregnancy test at screening and Study Day 1  
       (baseline visit) and may not be breast feeding 
Exclusion Criteria: 
1) Current severe disease (e.g. acute nephritis appropriate 
for induction therapy, CNS lupus (excepting chorea, 
cranial neuropathy, and resolving optic neuritis) or any 
lupus condition requiring cyclophosphamide, biologic 
therapy, or IV bolus steroids of >/= 500 mg. 
2) Subjects 
who 
are 
incapable 
of 
understanding 
or 

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completing study-related assessments. 
3) Subjects with any condition, whether or not related to SLE, 
which, in the opinion of the investigator, might place a 
subject at unacceptable risk for participation in the study. 
4) Subjects with a history of cancer in the last 5 years, other 
than non-melanoma skin cell cancers cured by local 
resection or carcinoma in situ.  
5) Subjects who currently abuse drugs or alcohol. 
6) Subjects with acute herpes zoster or cytomegalovirus 
(CMV)  within 2 months of screening. 
7) Subjects who have received any live vaccines within 3 
months of first dose. 
8) Subjects with any serious bacterial infection within the last 
3 months, unless treated and resolved with antibiotics, or 
any chronic bacterial infection (eg, chronic pyelonephritis, 
osteomyelitis, or bronchiectasis). 
9) Subjects at risk for tuberculosis (TB). 
10) Subjects known to be positive for hepatitis B surface 
antigen or hepatitis C unless negative by PCR or RIBA 
11) Acute hemolytic anemia with hemoglobin < 7.0 g/dL or 
known change in Hg by 2.0 g/dL within four months 
12) WBC < 2500/mm3 (< 3 x 109/L) unless due to chronic 
stable lupus activity  
13) Platelets < 40,000/mm3 (< 3 x 109/L) (If less than 100,000 
must have been stable (within a range of 10,000/mm3 ) 
within two months of screening or in two tests during the 
screening period. 
14) Serum creatinine > 2 times the ULN 
15) Serum ALT or AST > 2.5 times the ULN 
16) Any other laboratory test results that, in the opinion of the 
investigator, might place a subject at unacceptable risk for 
participation in the study. 
17) Known allergy/sensitivity to the study agent or carrier. 
18) Treatment with investigational drug within 28 days (or 5 
terminal half-lives) of the Day 1 dose.  
19) Cyclophosphamide within 3 months of Day 1 or bolus IV 
steroids >/=500 mg within 1 month 
20) Prednisone > 20 mg qd after the screening visit 
 
Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Efficacy: Primary endpoint will be response rates by “BICLA” 
(BILAG-based combined Lupus Assessment). Secondary efficacy 
endoints will be the SRI (SLE Responder Index), changes in 
SLEDAI, BILAG, PGA, CLASI, DIAL and PRO endpoints. Safety: 
Adverse Events, Serious Adverse Events and Adverse Events of 
special interest (infusion reactions and infections) will be collected 
and described. Stopping Rules: Patients may be withdrawn by 

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the investigator for non-compliance or safety. All patients 
terminating before six months will be considered non responders 
in the primary analysis. Use of off protocol immune suppressants 
will not necessarily dictate withdrawal but will determine non-
responder status. A DSMB board will review data on a quarterly 
basis and may stop the study if needed. 
Statistics: 
Primary Clinical Endpoint: proportion of patients on abatacept 
vs placebo who meet BICLA criteria at month 6 compared to 
baseline by Ch sq or Fishers Exact Test. Powering of the Study 
Based on the Primary Endpoint: Powering assumptions 
assume response rates ranging from 35-50%. based on data from 
patients with lupus arthritis in the Phase II abatacept study, where 
physicians rated 40% of the patients treated with abatacept as 
having “no flare.” Using the BICLA, response rates in the 
epratuzumab EMBLEM trial was also about 40% at optimal 
dosing, therefore this range seems applicable. Data from the 
BOLD study confirm that there should be a near zero (2.4%) 
percent response by BICLA at six months in the placebo group in 
a study with background IS withdrawal. Therefore our assumption 
of at least 5% response in the placebo group in an identical trial 
design is reasonable and with range of 40-50% response in the 
treatment group power > 0.8 to detect a difference.  Exploratory 
Analysis of Primary Endpoint: To address potential 
confounders in a small study a propensity score will be applied to 
simplify multiple variables into one variable.  
Secondary Clinical Endpoints: BICLA and SRI at each month. 
Mean SLEDAI, BILAG, CLASI, PGA, DIAL and PRO by paired T 
test. Main  Biologic Endpoint: Patients who do or do not exhibit 
proposed relative differences in the ratio of IL6/IL23/IL17 to 
Foxp3/TGFβ (suggesting T Cell signaling imbalance) or aberrant 
ErK phosphorylation (indicating abnormal signaling through B Cell 
receptor) at baseline will be compared for proportion of 
responders in treatment vs placebo group. Patients identified at 
baseline with high TH17 signal or ErK phosphorylation with >/= 
50% change towards healthy mean (+2SD) after treatment will be 
compared separately for response rates. These endpoints will be 
described in terms of confidence intervals based on the primary 
clinical endpoint. Analysis of Secondary and Exploratory Biologic 
Endpoints will include mean (or median) change in cytokine, 
immunoglobulin and gene expression levels explored based on 
known patterns of overexpression in SLE. Bucketing of baseline 
profiles might be used to develop propensity scores suitable for a 
simplified refinement of the primary biologic endpoint by 
combining variables that might either increase or decrease the 
likelihood of response. Given the complex array of data we are 
likely to generate, principal component analysis can be applied to 
these exploratory studies to identify directions (principal 
components) along which the variation of the data is maximal.  

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1 Introduction 
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by 
sporadic and often unpredictable flares of inflammation which can affect almost any organ in the 
body (1). The most common manifestations are polyarticular inflammatory arthritis, which can 
sometimes be disabling, and skin rashes which range from mild photosensitive eruptions to 
scarring, disfiguring discoid lesions. With current standard of care, many patients go through 
long periods of less than optimal disease control or be forced to take toxic immune 
suppressants or steroids, leading to significant morbidity (2). With optimal interventions some 
patients may be able to lead near normal lives for a long time but still be accruing significant 
damage to functional and vital organs, leading to long term disability and early mortality. Acutely 
severe and even life threatening flares can involve the kidneys, brain, heart, GI system, eyes, or 
lungs. Acquired immune-mediated hematologic disorders (cytopenias and microangiopathy) 
may also occur (1).  
Treatment development for lupus has been hampered by the heterogeneity of both underlying 
pathology and clinical manifestations (3,4). There is a growing appreciation that there is often a 
poor correspondence between the organ affected and the specific underlying complex 
pathology. Thus two people with renal disease may not respond to the same treatment(s) and 
similarly two given people lupus arthritis may require completely different approaches to 
therapy. Earlier trials for “general” lupus had limited options between problematic (but validated) 
endpoints, leading to arcane measurements of response that have caused some confusion 
between events which do or do not have clinical consequence. This was bound to cloud 
comparisons between an effective treatment and placebo, especially in a disease which is 
already clinically and biologically heterogenous. Further confounding this problem has been an 
understandable community reticence to subject potentially very ill patients to “true” placebo for 
long periods of time. Most year-long trials of lupus have allowed the use of such effective 
background and “rescue” treatments that endpoints become virtually uninterpretable (4). 
Abatacept has been evaluated for SLE by BMS in moderate sized Phase II clinical trials for 
nephritis and non nephritis SLE patients (5,6). Neither of these previously completed trials met 
primary or secondary endpoints, but exploratory analyses suggested that the problematic 
clinical endpoints (referred to above) and aggressive background treatments might have 
impaired the interpretation of these studies. Some modifications in clinical trial design for SLE 
have been recently tested (7-9) suggesting that careful selection of endpoint(s) and minimizing 
background therapies (with an immediate and effective rescue strategy that itself can define 
non-response) provides an ethical study with improved discriminatory capacity despite the 
complexity of the underlying disease. The current application proposes a small trial with an 
immune suppressant withdrawal strategy coupled to endpoints which have been shown to 
provide maximal discriminatory capacity by minimizing the “noise” of minor improvements and 
clinically insignificant disease flares, thus decreasing artifactual response and artifactual non-
response. This study will also explore the possibility that biomarkers might be identified to define 
subsets of patients as appropriate candidates for this targeted treatment and to guide optimal 
dosing for such definable candidates.  

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No targeted therapy can be expected to work for all patients in a disease with such 
heterogenous underlying biology. There is thus an inevitable low ceiling on the percentage of 
patients likely to respond if they are entered into a trial without biology-based pre-qualification 
steps. Although the current trial is designed to maximize effect size between treatment and 
placebo there is little that can be done to increase the inevitable 50% limit on response rates of 
targeted biologics, regardless of the discriminatory capacity of the endpoints.  For this reason, 
biomarker discovery to provide a more meaningful basis for selecting patients for targeted 
treatments should be a high priority both for optimizing patient care and for the appropriate 
dissemination of treatments that are not “first to market.” As more biologic treatments enter the 
field, strategic biomarker-based matching of treatments and individual patients may help to 
ensure a competitive effect size, gain faster approval at less expense, gain more rapid 
penetration and retention of the optimal (and medically most appropriate) market, and convince 
third party payers of the utility of a treatment.  
 
1.1 
Pathology of SLE:  
SLE is a prototypic complex autoimmune disease which may arise through imbalances in 
inherited variants throughout the immune system (10,11). The exact pattern of resulting immune 
imbalance may vary among patients, but there are strong tendencies for hyperstimulation of 
Toll-Like Receptor, Interferon alpha regulated signals, and aberrant T and B cell mediated 
pathways which results in a characteristic pattern of autoantibody production and complement 
activation (10-12). At the same time, regulatory elements of immunity seem to be dampened, 
including T suppressor activity and immune clearance by myeloid cells (13,14). The net result is 
sporadic but refractory inflammation in various organs. 
 
1.2 
Relevance of Abatacept Mechanism to Lupus 
Genetics studies and studies in twins have demonstrated that Class II major histocompatibility 
complex (MHC) plays an important role in contributing to the susceptibility and/or severity of 
rheumatic diseases (15). MHC molecules are prominent on antigen presenting cells, and it is 
the MHC molecule that binds antigen in its “antigen-binding groove” to “present” the antigen to 
the T cell’s antigen receptor.  
Abatacept was originally developed to finely target T Cell costimulation by blocking the signals 
between CD 28 and CD80/86. This would be predicted to have effects on both B and T cells as 
has been borne out in both animal and human studies (16,17). In human RA rheumatoid factor 
is reduced after 12 months of abatacept therapy suggesting an impact on B Cell activation and 
autoantibody production (16). Ag-specific T cell proliferation is reduced, and development of an 
activated T cell phenotype with upregulation of CD69, and ICOS can be suppressed with 
abatacept (17). Modulation of a number of related inflammatory cytokines by abatacept have 
been described in patients with RA, some of which might be of critical relevance in SLE. These 
include reduction of serum interleukin 6 (IL-6) (17), IFN-gamma and IL-17 and a failure of Ag-
specific T cells to acquire the CXCR5(+) ICOS(+) T follicular helper cell phenotype (17). 
When a targeted agent is applied to the background of SLE immune dysequilibrium, it cannot be 
assumed to net the same changes in immune balance seen in RA.  However preliminary data 
support some similar patterns in SLE of suppression of B Cell autoantibody production and 
modulation of T Cell differentiation.  In SLE, B cells express increased IL-6 that can 
autostimulate terminal differentiation of the low density B Cell subsets leading to increased 
autoantibody production.(17)  Data from the Phase II study of abatacept in general SLE 

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suggests that IL-6 levels are  depressed in abatacept treated patients but not placebo patients 
during flare and abatacept  consistently decreases anti-dsDNA antibodies (5) (see figure below). 
A similar trend was seen in the Phase II nephritis study, with abatacept-treated patients 
maintaining decreased anti-dsDNA levels after steroid tapering unlike placebo, with expected 
dampening of complement consumption (6). The exact pathway(s) might connect that apparent 
connection between IL6 and autoantibodies have yet to be fully sorted out, but IL6 can mediate 
significant changes in T Cell differentiation patterns, leading to increased IL-17, which 
accentuate B cell activation and proliferation, antibody production and class switching (18,19). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On the basis of these data we speculate that expected biologic effects of abatacept in SLE 
should include decreases in known volatile autoantibodies such as anti-dsDNA and 
anticardiolipin, accompanied by signals relevant to terminal B Cell differentiation and the 
IL6/IL23/TH17 pathway. The usual relative upregulation of TH17/Tregulatory pathways in 
SLE might be reversed. These expected changes will be tested to define the most likely 
responder group prior to treatment, and explore pharmacodynamic changes in responders after 
treatment, helping to confirm whether such pharmacodynamic predictors of dose-target efficacy 
are related to clinical efficacy.  Furthermore we hypothesize that biomarkers of B cell 
activation such as Erk phosphorylation will be depressed with CTLA4Ig therapy and that 
elevation of these markers pre-treatment will predict responders to therapy and a change in the 
relative balance of these elements in those pre-defined patients will provide an even better 
predictor of response.  
 
These endpoints will serve as major biologic endpoints (which are secondary endpoints of the 
study (see below). In exploratory analysis we will also examine unforeseen patterns of gene 
expression in B Cell and T Cell subsets before and after treatment with abatacept. The biologic 
endpoints proposed here will employ techniques that have been widely published in human 
subjects (20-26). Additionally samples of RNA, DNA, and serum and/or plasma will be saved for 
both pre-specified and exploratory research at OMRF or BMS. 
 
One major hypothesis is that abatacept may affect the elevated ratio of IL6/IL23/IL17 (and 
associated TH17 pathway signals) to Foxp3/TGFβ. Abatacept would be expected to function 
-200
-150
-100
-50
0
50
100
15
29
57
85
113
141
169
197
225
253
281
309
337
365
U/mL
Day
Abatacept
Placebo
0
2
4
6
8
10
12
2 months pre-flare
1 month pre-flare
During flare
pg/mL
Abatacept
Placebo
Change From Baseline in anti 
dsDNA levels   
Red represents Abatacept-treated 
patients and Blue are  Placebo-
treated patients. X axis=serial visits in 
the (Phase II non-nephritis trial, 
reference 8)                             
 
Abatacept May Suppress IL-6 
Production These are BMS data 
showing that even when abatacept 
study   treated SLE patients flare the 
expected IL-6 increase, seen in the 
placebo pts (light blue bars), does not 
occur. 

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downstream of IL6, this type of signal inconsistency would be a major indicator of abatacept 
effects as opposed to an effect of rescue steroids that might be given in the study. Based on 
work by Tsokos et al (a close advisor to our group) (20) we will be performing a gene 
expression array aimed at detecting the relevant abnormalities in a subset of our patients and 
tracking abatacept effects on this ratio. As an exploratory biologic analysis, our collaborative 
groups will also pursue a finding from gene expression profiling in the BOLD study. Ongoing 
analyses are showing that increased disease activity, cluster with elevated levels of iCOS 
(CD275) and iCOSL (CD279). iCOS is the third member of the CD28 T cell co-stimulatory 
pathway (with CD28 and CTLA4) leading to interesting questions in how these expression 
patterns will be modified with abatacept therapy and whether these patients will be more 
responsive to abatacept therapy.  
 
We will apply either a parallel approach to explore gene expression profile information from 
whole blood of SLE patients before and after abatacept therapy, or will expand these studies to 
use RNAseq approaches which are currently in use in our laboratory to allow assessment of 
gene expression levels but also of long noncoding, regulatory and viral RNAs in the same 
experiment. 
 
In ongoing collaborative work, our groups have shown that SLE patients who are experiencing a 
flare even on background medications have evidence of elevated shed TNF receptors 
supporting increased B cell activation (e.g. TNFRI, TNFRII, sFASL and sFas), as well as other 
inflammatory cytokines (see Fig below). These results demonstrate the elevated levels of these 
shed receptors in the flare visits compared to the same individuals at non-flare timepoints, as 
well as to other control SLE patients who did not flare in the same study (matched for age, race 
and gender). These results are interesting; however, every SLE patient does not act the same 
and the current study will allow us to assess whether shedding (and associated B cell activation) 
correlates with better SLE abatacept clinical response and whether other background 
immunomodulatory medications at baseline might influence these plasma cytokine patterns. 
Evaluation of frozen cells has also showed that SLE patients who were having a clinical flare 
have increased responses to B cell receptor signaling as is measured by phosphorylated ERK 
levels in BCR stimulated responses compared to BCR unstimluated. Again, this activation was 
seen in the same individuals during a flare compared to a nonflare visit, as well as compared to 
control SLE patients who did not flare. Parallel approaches will assess the role of abatacept on 
B cell activation, as well as to assess whether patients elevated pERK responses to BCR 
engagement are more likely to be responders to abatacept therapy. 
 
 

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We conclude that disease activity can be linked to characteristic patterns of plasma 
biomarkers, cellular responses and gene expression profiles using a principal 
component analysis from a cell lineage-specific panel based on known pathogenic 
mechanisms. We will test this hypothesis in the proposed clinical trial with an exploratory 
analysis of changes in both B Cell and T Cell expression profiles. Pre-specified analyses will 
include evaluation of B cell activation as measured by ERK phosphorylation after BCR signaling 
and the fuller gene expression in B and T Cells that is related to the signal impact of IL6, TH17, 
and iCOS which are expected to be affected by abatacept. Plasma levels of BLyS and TNFRs 
will also be explored. 
 
IL-1
2
4
6
0
pg/ml
IL-8
5
10
15
0
pg/ml
IL-13
20
40
60
80
0
pg/ml
IP-10
0
1
2
3
ng/ml
IL-4
Flare
Nonflare
Control
5
10
15
0
pg/ml
* 
* 
* 
** 
* 
* 
* 
* 
* 
** 
sFas
500
1500
0
1
2
ng/ml
sFasL
Flare
Nonflare
Control
0
0.2
0.4
0.6
ng/ml
* 
* 
* 
* 
TNFRI
0
1
2
3
4
5
ng/ml
TNFRII
Flare
Nonflare
Control
0
1
2
3
4
5
6
ng/ml
** 
*** 
* 
*** 
*** 
* 
Flare
No flare
Control
0
1
2
3
Phosphorylated  ERK
BCR stim/unstimulated
*
*
*

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14 
 
 
 
 
1.3 
Summary of Results of Investigational Program 
1.3.1 
Pharmacology of Abatacept 
Abatacept is a recombinant fusion protein of the extracellular domain of human CTLA4 and a 
fragment (hinge- CH2-CH3 domains) of the Fc domain of human IgG1 that has been modified to 
prevent complement fixation and antibody-dependent cellular cytotoxicity. Consistent with the 
known biologic activity of CTLA4, Abatacept binds to CD80 (B7-1) and CD86 (B7-2), which are 
co-stimulatory molecules on the surface of antigen-presenting cells (APCs) which reinforce 
cognate interactions between B and T Cells. These are commonly bound by CD28, which is 
constitutively expressed on resting T cells.(15,27-29).  A costimulatory signal allows activation 
of naive T cells in the context of antigen presentation, and promotes the survival of memory and 
autoimmune effector cells (15, 27). At 24 to 48 hours following T cell activation, the T cell 
expresses CTLA4 on its surface, which preferentially binds the CD80 and CD86 molecules with 
high affinity, interfering with the CD28 signal. This is associated with decreased T Cell 
activation. The CTLA4 section of abatacept binds to CD80 and CD86 and down-modulates the 
CD28-mediated costimulation of T cells. The FC region of abatacept has several point 
mutations to inhibit antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity 
(15). 
 

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1.3.2  Human Pharmacokinetics of Abatacept 
 
Support for SC dosing route: Single subcutaneous (SC) dose study  of abatacept 
(50 to 150 mg) where escalating, single, fixed doses were administered demonstrated 
approximately dose proportional PK in healthy adult subjects based on the geometric means of 
Cmax and AUC(INF) values (30).  The median time to occurrence of Cmax (Tmax) following SC 
administration ranged between 48-168 hours. Mean T1/2 values in healthy subjects ranged 11.2 
to 14.7 days, which was comparable with the T1/2 values obtained with abatacept administered 
IV to subjects with RA (13 to 14 days) (30) The fact that T1/2 values following SC dosing were 
comparable to T1/2 values obtained after IV dosing suggests that the SC administration did not 
alter elimination of abatacept. 
 
Although subcutaneous administration has not been studied previously in SLE, key information 
about subcutaneous dosing of abatacept in a comparable population can be inferred through 
data from the IM101063 trial in rheumatoid arthritis. A double-blind, randomized, placebo-
controlled, parallel-group, multiple-dose study (IM101063) assessed the steady-state trough 
serum concentrations of abatacept following SC administration in subjects with RA (31). 
Subjects were randomized to receive either abatacept or placebo in 1 of 5 parallel groups based 
on body weight obtained at the screening visit (Table 1.3.2A). The SC dose regimens were 
selected to target trough levels between 10-30 g/mL, which was associated with efficacy with 
the IV formulation. 
 
Table 1.3.2A 
Treatment Groups Based on Body Weight- IM101063 
Treatment 
Group 
Subject weight 
(kg) 
IV dose on  
Day 1 (mg) 
SC dose weekly for 
12 weeks (mg) 
SC injection volume 
(mL) 
1 
< 60 
500 
75 
0.6 
2 
< 60 
500 
125 
1 
3 
60 - 100 
750 
125 
1 
4 
> 100 
1000 
125 
1 
5 
> 100 
1000 
200 
0.6 + 1.0 
Source: IM101063 Clinical Study report, Table 3.1 (31). 
 
On Day 1, subjects received a single IV infusion (loading dose) of abatacept or placebo, based 
on their weight range. Approximately 1 hour after the completion of the IV infusion, subjects 
received their assigned SC dose of abatacept or placebo. Abatacept or placebo was 
administered weekly by the SC route, at the same dose as the SC dose on Day 1.  
 
Steady-state trough serum concentrations were achieved after ~ 4 to 5 weeks following the 
combined regimen of a single IV loading dose and weekly SC injections. To truly represent the 
steady-state serum levels from SC administration without the contribution of the IV loading 
dose, Cmin values on Days 71-85 were selected, since contribution from IV was expected to be 
negligible. 
 
Table 1.3.2B describes the summary statistics of abatacept Cmin values achieved from Day 71 
to Day 85. ).  
 

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16 
 
Table 1.3.2B: 
Summary Statistics for Abatacept Steady-State 
Cmin Values on Days 71, 78, and 85 - IM101063 
 
Treatment Group 
Study Day 
n 
Cmin (g/mL) 
Geometric Mean (CV%) 
Cmin (g/mL) 
Median (Min, Max) 
1 (500 mg IV / 75 mg SC) 
71 
7 
22.64 (20.13) 
20.92 (17.06, 29.84) 
 
78 
7 
21.66 (19.99) 
22.40 (16.01, 28.93) 
 
85 
7 
23.62 (31.63) 
21.91 (18.24, 39.60) 
2 (500 mg IV / 125 mg SC) 
71 
4 
28.03 (42.13) 
32.57 (13.73, 43.30) 
 
78 
3 
34.17 (29.49) 
33.10 (25.97, 46.40) 
 
85 
3 
36.73 (31.64) 
37.50 (26.26, 50.30) 
3 (750 mg IV / 125 mg SC) 
71 
26 
24.05 (40.65) 
26.53 (7.97, 54.11) 
 
78 
23 
24.41 (52.35) 
27.54 (5.40, 68.90) 
 
85 
25 
24.93 (38.42) 
26.01 (9.57, 53.80) 
4 (1000 mg IV / 125 mg SC) 
71 
3 
16.22 (24.39) 
15.15 (13.37, 21.07) 
 
78 
5 
11.57 (32.25)  
13.20 (6.89, 16.33) 
 
85 
5 
13.01 (41.35) 
13.30 (6.66, 22.73) 
5 (1000 mg IV / 200 mg SC) 
71 
5 
26.52 (56.53) 
26.20 (8.68, 55.20) 
 
78 
5 
29.21 (52.96) 
40.40 (8.04, 57.10) 
 
85 
5 
27.53 (58.87) 
29.01 (8.74, 62.00) 
Source:  IM101063 Clinical study report, Table 9.2. (31) 
 
Systemic exposure of SC abatacept in terms of the distribution of Cmin was comparable across 
treatment groups. Geometric mean or median steady-state trough (Cmin) values were 
comparable for Treatment Groups 1, 3, and 5 and the Cmin values for Treatment Groups 2 and 
4 appeared to be higher and lower, respectively, than the observed values associated with the 
other Treatment Groups.  
However, the range of the steady-state trough concentrations in the Treatment Groups 2 and 4 
was within the range of trough concentrations achieved in Treatment Group 3 (Please refer to 
Figure 1.3.2A, shown on the following page).  
 

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Figure 1.3.2A: 
Scatter Plot of Individual Steady-State Cmin Values from Days 71 to 
85 by Treatment Group - IM101063 
 
Source: Clinical study report IM101063, Figure 9.2.2 (31)  
Table 1.3.2C 
Summary Statistics for Abatacept Steady-State 
Pharmacokinetic Parameters - IM101063 
Treatment Group 
Pharmacokinetic Parameter 
Cmax (µg/mL)  
Geometric Mean (CV%) 
AUC(TAU) (µg*h/mL) 
Geometric Mean (CV%) 
1 (500mg IV / 75mg SC) 
n = 7  
26.3 (29.5) 
n = 7 
4066 (22.2) 
2 (500mg IV / 125mg SC) 
n = 4 
34.9 (46.6) 
n = 3 
6699 (20.7) 
3 (750mg IV / 125mg SC) 
n = 26 
31.9 (42.8) 
n = 24 
4607 (38.6) 
4 (1000mg IV / 125mg SC) 
n = 5 
14.7 (44.3) 
n = 4 
2555 (30.1) 
5 (1000mg IV / 200mg SC) 
n = 5 
41.7 (41.2) 
n = 5 
5849 (40.5) 
Source: IM101063 Clinical study report, Table 9.3. (31) 
n = number of subjects, TAU = 7 days 
TRT 1
TRT 2
TRT 3
TRT 4
TRT 5
Serum abatacept concentration (µg/mL)
0
10
20
30
40
50
60
70
80
TRT 1 (75 mg/ <60 kg): n=21 data points (from 7 subjects), median = 21.9 µg/mL 
TRT 2 (125 mg/ <60 kg): n=10 data points (from 4 subjects), median = 35.2 µg/mL 
TRT 3 (125 mg/ 60-100 kg): n=75 data points (from 29 subjects), median = 26.6 µg/mL 
TRT 4 (125 mg/ >100 kg): n=13 data points (from 5 subjects), median = 13.4 µg/mL 
TRT 5 (200 mg/ >100 kg): n=15 data points (from 5 subjects), median = 29.0 µg/mL 
Dark circles (•) represent median values 
 

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18 
 
 
Support for Selection of fixed 125 mg SC dosing in RA 
 
Accumulated data from BMS (32-33) confirming efficacy and safety results of SC abatacept 
across RA patients of various rates, supports the study of 125 mg SC in lupus patients.  
 
The SC dosing regimen of abatacept was constructed using an integrated assessment of PK, 
PD, and clinical efficacy and safety data from in vitro, nonclinical and clinical studies. The SC 
dose was optimized in Phase 2 to target trough concentrations of  10 g/mL in > 90% of 
subjects with RA in order to assure efficacy similar to IV abatacept without any detrimental 
effects on safety. The E-R relationships and the totality of clinical efficacy and safety data from 
the Phase 3 Study IM101174 demonstrated that the fixed dose regimen of SC abatacept 125 
mg weekly and the monthly regimen of IV abatacept (500, 750, and 1000 mg for subjects 
weighing < 60 kg, 60 to 100 kg, and > 100 kg, respectively) were therapeutically equivalent for 
the treatment of RA for the following reasons: 
• 
Despite differences in systemic exposure between SC and IV administration of abatacept, 
steady-state Cmin concentration of 10 g/mL or higher, which was associated with near 
maximal efficacy, was achieved in subjects of all body weights following both IV and SC 
administration. 
− 
Abatacept Cmin concentrations were comparable between SC and IV treatments in 
subjects weighing > 100 kg, and the efficacy response in this weight group was 
comparable between the SC and IV abatacept treatments, demonstrating that efficacy 
was not compromised in heavier subjects. 
• 
The clinical efficacy results from the IM101174 study further validated the selection of the 
fixed-dose SC abatacept regimen, which demonstrated that SC abatacept is non-inferior to 
IV abatacept.  
• 
In the comparative SC/IV population (IM101174) and the cumulative SC period the 
frequencies of adverse events, deaths, serious adverse events, adverse events/serious 
adverse events leading to discontinuation, and adverse events of special interest were 
consistent with the established safety profile of IV abatacept; no new safety signals were 
identified for SC abatacept.  
− 
Additionally, exposure-safety analyses demonstrate that there is no evidence of a 
relationship between abatacept systemic exposure and probability or time-to-event of 
infections, or the probability of serious infections. 
• 
Results confirmed that administration of SC abatacept has a similar, low immunogenic 
profile to that observed with IV abatacept.  
• 
Analysis of clinical response data from the non-inferiority Study IM101174 showed that no 
clinically relevant differences in the profiles of SC abatacept vs. IV abatacept with respect to 
efficacy, safety, and immunogenicity could be detected within weight groups defined by 
baseline body weight (either based on quartiles or on the IV weight-tiered dosing strategy 
[under 60 kg, 60 to 100 kg, and over 100 kg]).  
The SC dosing regimen of abatacept was constructed using an integrated assessment of PK, 
PD, and clinical efficacy and safety data from in vitro, nonclinical and clinical studies. The SC 
dose was optimized in Phase 2 to target trough concentrations of  10 g/mL in > 90% of 
subjects with RA in order to assure efficacy similar to IV abatacept without any detrimental 
effects on safety. The E-R relationships and the totality of clinical efficacy and safety data from 

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19 
 
the Phase 3 Study IM101174 demonstrated that the fixed dose regimen of SC abatacept 125 
mg weekly and the monthly regimen of IV abatacept (500, 750, and 1000 mg for subjects 
weighing < 60 kg, 60 to 100 kg, and > 100 kg, respectively) were therapeutically equivalent for 
the treatment of RA for the following reasons: 
 
• 
Despite differences in systemic exposure between SC and IV administration of abatacept, 
steady-state Cmin concentration of 10 g/mL or higher, which was associated with near 
maximal efficacy, was achieved in subjects of all body weights following both IV and SC 
administration. 
− 
Abatacept Cmin concentrations were comparable between SC and IV treatments in 
subjects weighing > 100 kg, and the efficacy response in this weight group was 
comparable between the SC and IV abatacept treatments, demonstrating that efficacy 
was not compromised in heavier subjects. 
 
• 
The clinical efficacy results from the IM101174 study further validated the selection of the 
fixed-dose SC abatacept regimen, which demonstrated that SC abatacept is non-inferior to 
IV abatacept.  
 
• 
In the comparative SC/IV population (IM101174) and the cumulative SC period the 
frequencies of adverse events, deaths, serious adverse events, adverse events/serious 
adverse events leading to discontinuation, and adverse events of special interest were 
consistent with the established safety profile of IV abatacept; no new safety signals were 
identified for SC abatacept.  
− 
Additionally, exposure-safety analyses demonstrate that there is no evidence of a 
relationship between abatacept systemic exposure and probability or time-to-event of 
infections, or the probability of serious infections. 
 
• 
Results confirmed that administration of SC abatacept has a similar, low immunogenic 
profile to that observed with IV abatacept.  
 
• 
Analysis of clinical response data from the non-inferiority Study IM101174 showed that no 
clinically relevant differences in the profiles of SC abatacept vs. IV abatacept with respect to 
efficacy, safety, and immunogenicity could be detected within weight groups defined by 
baseline body weight (either based on quartiles or on the IV weight-tiered dosing strategy 
[under 60 kg, 60 to 100 kg, and over 100 kg]).  
 
Effect of IV loading dose on abatacept trough concentration in RA 
 
The majority of clinical data from the SC abatacept program is associated with the 
administration of an IV loading dose to initiate therapy with SC abatacept, including the results 
from the IM101174 noninferiority study. At the time of initiation of this study, the instantaneous 
achievement of serum concentrations above 10 µg/mL was thought to be needed in order to 
provide an optimal comparison between the IV and SC regimens. 
However, parallel studies were conducted to assess the impact and need of this IV loading dose 
in the proposed SC regimen. There is limited clinical data from 2 trials, IM101173 (n = 100) and 

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20 
 
IM101167 (n=76), where subjects did not receive an IV loading dose prior to initiation or re-
initiation of SC abatacept therapy. 
In addition to the observed clinical data, simulations were performed using the PPK model to 
evaluate the distribution of Cmin with respect to time when SC abatacept was administered 
without an IV loading dose.  In the absence of the IV loading dose, steady-state trough serum 
concentrations were achieved after 6 to 8 weeks of weekly SC abatacept administration and 
88% of subjects achieved Cmin concentrations of 10 μg/mL or higher within 2 weeks of SC 
dosing.  
 
The IV loading dose of abatacept was proposed for clinical evaluation in order to offset the initial 
low serum concentrations expected immediately following SC dosing alone. While the IV loading 
dose of abatacept is recommended prior to the initiation of SC abatacept, the PK data from 
IM101173 and IM101167 and PPK modeling and simulations suggest that target serum trough 
concentrations of 10 g/mL, which are associated with near maximal efficacy, could potentially 
be reached in 88% of subjects within 2 weeks of dosing with SC abatacept alone.  
The efficacy, safety, and immunogenicity of SC abatacept were also evaluated across studies 
when SC abatacept was administered without an IV loading dose. In two open-label studies 
IM101173 and IM101167 (Period I), albeit slightly different disease severities at baseline, 
DAS28-CRP decreased comparably over time, up to Day 85, when SC abatacept was 
administered with (IM101167) or without (IM101173) the initial IV loading dose on Day 1. 
Treatment with SC abatacept 125 mg weekly in the absence of an IV loading dose was well 
tolerated by subjects with RA in study IM101173. The safety profile for SC abatacept during the 
ST and LT periods of IM101173 was consistent with the known safety profile for abatacept. 
There was no significant increase in immunogenicity rates or antibody titers when SC abatacept 
was administered in the absence of an IV loading dose (IM101173).   
The combined, albeit limited, data from PK, clinical efficacy, safety, and immunogenicity suggest 
that the loading dose of IV abatacept may not be necessary for initiation or restarting SC 
abatacept. 
 
1.3.3 Clinical Safety of the Abatacept IV Formulation in SLE and of the 
SC Formulation in RA 
In the year long non nephritis Phase II lupus study (IV formulation) (5), the percentage of 
patients with any AEs was comparable between the abatacept and placebo groups (90.9 and 
91.5% respectively.  Ten (8.3%) and three (5.1%) patients in the abatacept and placebo groups 
discontinued due to AEs. The most frequently reported AEs (>10% patients in either group) 
were upper respiratory tract infection (25 [20.7%] vs 9 [15.3%]), headache (25 [20.7%] vs 10 
[16.9%]), back pain (15 [12.4%] vs 5 [8.5%]), diarrhea (14 [11.6%] vs 4 [6.8%]), nasopharyngitis 
(3 [2.5%] vs 7 [11.9%]) and urinary tract infection (13 [10.7%] vs 5 [8.5%]) in the abatacept and 
placebo groups, respectively. This is summarized in the table below 
 
 

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21 
 
 
Table 1.3.3a. Safety summary over 1 year  
  
Abatacept 
n=121 
n (%) 
Placebo 
n=59  
n (%) 
Adverse events  
110  (90.9)         
54  (91.5) 
Treatment-related adverse events 
59  (48.8)          
28  (47.5) 
Discontinuations due to adverse events* 
10   (8.3)          
3   (5.1) 
Serious adverse events  
24  (19.8)          
4   (6.8) 
Treatment-related serious adverse events 
7   (5.8)           
2   (3.4) 
Discontinuations due to serious adverse events* 
7   (5.8)           
1   (1.7) 
Deaths 
1   (0.8)           
0 
* AE=adverse event;  
 
Serious infections were reported in three abatacept-treated patients and one placebo-treated 
patient in this study. One abatacept patient was admitted to hospital with bronchitis which 
resolved allowing the patient to continue the study treatment. One abatacept-treated patient 
developed nausea, vomiting and abdominal pain, and a presumptive diagnosis of diverticulitis 
was reported on Day 362. This SAE also resolved and the patient continued in the study. One 
patient had gastroenteritis on Day 333, which the treating physician considered to be of mild 
intensity; abatacept was discontinued. Bronchopneumonia was reported in one patient in the 
placebo group.  
 
Serious AEs of glomerulonephritis, mesangioproliferative glomerulonephritis and lupus nephritis 
occurred in one patient each in the abatacept group. The glomerulonephritis and mesangio-
proliferative glomerulonephritis were deemed unrelated to study drug and occurred in patients 
with renal medical history. The case of glomerulonephritis was reported after the patient had 
discontinued due to lack of efficacy on Day 147. The patient was hospitalized on Day 172 with 
severe alveolitis, and proteinuria of 1.3 g/day was recorded and a renal biopsy showed “mild 
glomerulonephritis.”  Moderate mesangio-proliferative glomerulonephritis was reported in a 
patient hospitalized with renal flare who discontinued study drug. “Lupus nephritis” was reported 
in a patient after three doses of abatacept. The patient was hospitalized for increased 
proteinuria, with biopsy c/w Class II. The investigator considered this unlikely related to study 
treatment.  
 
In the SLE nephritis study (6), with 298 subjects, abatacept was apparently well tolerated 
compared to patients receiving background therapy. This was a more ill patient population than 
the Phase II non nephritis trial and mycophenolate mofetil was used in all patients along with 
significant steroids. The percentages of patients with adverse events (AEs) and serious AEs 
(SAEs) were similar among the three treatment groups, with infections being the most 

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22 
 
commonly reported. However more gastro-enteritis and herpes zoster occurred in abatacept 
treated patients compared to placebo. 
 
Fourteen patients died in the double-blind treatment period in the nephritis study; 7 of these 
were related to an infection (4 placebo; 3 abatacept 30/10 mg/kg; 1 abatacept 10/10 mg/kg). 
Thus, although Abatacept did not seem to increase risk of infection when added to 
mycophenolate, that risk appeared higher in this group than in the non-nephritis lupus 
population studied with abatacept and various background treatments. The current population, 
should be similar to the latter group, and background immune suppressives, including 
mycophenolate where it is being used, will be universally withdrawn, with less steroids 
mandated than in either of the previous abatacept studies. 
 
 Table 1.33b. Summary of serious adverse events in the nephritis study 
Abatacept 30/10  
(n=99) 
Abatacept 10/10 
(n=99) 
Placebo  
(n=100) 
Deaths, n (%)  
5 (5.1)  
2 (2.0)  
7 (7.0)  
SAEs, n patients (%) 
Infections 
Pneumonia 
Herpes zoster 
Gastroenteritis 
Urinary tract infection 
Renal failure 
33 (33.3) 
23 (23.2) 
4 (4.0) 
3 (3.0) 
5 (5.1) 
0 
3 (3.0) 
28 (28.3) 
18 (18.2) 
4 (4.0) 
6 (6.1) 
1 (1.0) 
2 (2.0) 
2 (2.0) 
31 (31.0) 
17 (17.0) 
3 (3.0) 
0 
2 (2.0) 
2 (2.0) 
3 (3.0) 

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23 
 
 
SAEs seen in the non-nephritis study were predominantly attributed to the underlying disease of SLE 
and generally reflected single events not localized to a specific organ system. A Data Monitoring 
Committee (DMC) regularly reviewed emerging efficacy and overall safety data to ensure appropriate 
benefit-risk. The DMC recommended discontinuation of open label study because of failure to meet 
the primary outcome measures in face of increased SAEs.  
In the non-nephritis study, (most similar to the patient population to be studied here), serious adverse 
events occurred in (24 [19.8%] of the patients treated with abatacept vs 4 [6.8%] of the placebo 
patients. . Of these, seven (5.8%) and 1 (1.7%) patients discontinued the study due to SAEs in the 
abatacept and placebo groups, respectively. SAEs are reviewed in the table below, and generally 
provide some reassurance that with careful monitoring this medication might be given with reasonable 
safety to this population.  
 
Table 1.33c. Breakdown of Serious SAE Categories from the non-nephritis lupus trial 
by Medical Dictionary for Regulatory Activities (MedDRA)  
  
Abatacept 
n=121 
n (%) 
Placebo 
n=59  
n (%) 
Total patients with serious adverse events 
24 (19.8) 
4 (6.8)  
Musculoskeletal and connective tissue disorders  
6 (5.0)  
1 (1.7)  
General disorders and administration site conditions 
4  (3.3) 
0 
Infections and infestations 
3 (2.5) 
1 (1.7)  
Renal and urinary disorders 
3  (2.5) 
0  
Gastrointestinal disorders 
2  (1.7) 
1  (1.7)  
Nervous system disorders 
2  (1.7) 
1  (1.7) 
Psychiatric disorders 
2  (1.7) 
1  (1.7) 
Cardiac disorders 
2 (1.7) 
0  
Immune system disorders 
2 (1.7) 
0  
Injury, poisoning and procedural complications 
2 (1.7) 
0 
Respiratory, thoracic and mediastinal disorders 
2 (1.7) 
0 
Blood and lymphatic system disorders 
1 (0.8) 
0 
Metabolism and nutrition disorders 
1 (0.8) 
0 
Skin and subcutaneous tissue disorders 
0 
1 (1.7) 
Vascular disorders 
0 
1 (1.7) 
 

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24 
 
 
Table 1.33d Specifics of Serious Adverse Events in Phase II IV Non-nephritisTrial Population Similar to 
Those to be Recruited into the Current Study 
 
Patient 
Event VT/PT            
Description               
1.  009 
Abdominal pain   
Mild lower abdominal pain; seen in ER; exam normal; 
discharged one day later                                                    
2.  260  
Costal pain/ Musculoskeletal 
chest pain 
Admitted to hospital for bone scan to evaluate 
abnormalities seen on radiographs. Discharged next 
day. 
3. 6 
 
Systemic lupus flare/SLE 
Admitted to hospital for 2 days for lupus flare: facial 
erythema, vasculitic lesions on finger, and 
polyarthralgias. Study drug discontinued. 
4. 150  
Fever due to SLE flare 
up/SLE     
Fever, facial rash; admitted to hospital for treatment via 
ER.   
5. 106  
Fever one day/Pyrexia 
One day fever, general discomfort, elevated liver 
enzymes.  Admitted for R/O sepsis, lupus flare or 
hepatitis.  Treated with abx and IV steroids. Presumed 
lupus flare.  Study drug discontinued. 
6. 196 
Facial edema/Face oedema  
Hand edema/Oedema 
peripheral 
Fever/Pyrexia 
Admitted with fever, facial, hand and peripheral edema. 
Treated with high dose prednisone and abx for 
presumed lupus flare vs. infection.  Study drug 
discontinued. 
7. 93 
Angio-edema/Angioedema 
 
Lupus exacerbation/ SLE 
 
 
Severe lupus activity + 
vasculitis/ Lupus vasculitis
 
 
Facial swelling and myalgias  after second study drug 
infusion.  Study discontinued.  
 
Diffuse pain thought to be due to lupus activity.  
Treated with high dose prednisone.  
 
No details on the event; close in time to lupus 
exacerbation SAE. 
8. 185 
Lupus nephritis 
 
Admitted for evaluation of increasing proteinuria 
(present at baseline); biopsy performed and Class III 
nephritis.  Study drug discontinued after only month of 
therapy. 
9. 11  
Bronchopneumonia 
 
 
 
Psychosis/Psychotic disorder 
Ongoing bronchitis worsened; CXR revealed probable 
bronchopneumonia. Treated with IV abx and improved. 
 
 Acute psychosis/mental deterioration thought due to
 
lupus.  Study drug discontinued and started on 
cyclophosphamide IV and azathioprine. 
10. 30  
Gastroenteritis 
Gastroenteritis symptoms; admitted for 3 days for 
unknown treatment and discharged. 
11. 88  
Pericarditis 
Admitted with lupus flare; CT of chest showed 
pericardial effusion.  Treated with high dose 
prednisone.  Resolved in 3 weeks.  Study drug 
interrupted. 
12. 173 
Alveolitis 
 
 
 
Hospitalized for progressive dyspnea; suspected 
alveolitis due to lupus.  Study drug discontinued.  
Patient started on high dose prednisone  
 

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Glomerulonephritis 
During hospitalization for alveolitis, found to have 
increased proteinuria.  Biopsy revealed non-specific 
glomerulonephritis.  Started on MMF. 
13. 103 
Worsening of 
anemia/Anemia 
Fever/Pyrexia 
Admitted for worsening anemia and chronic fever. 
Fevers not confirmed during hospitalization.  Work-up 
for  
infection negative.  Anemia work-up also non-
revealing; thought to be iron deficiency anemia.  Study 
drug interrupted 
14. 129 
Headache 
Unremitting headache with nausea and vomiting.  
Hospitalized 3 days for unspecified treatment. 
15. 116 
Polyneuropathy 
Patient developed parasthesias in hands and feet. 
EMG showed symmetric polyneuropathy.  Study drug 
discontinued. 
16. 163 
Allergy/Hypersensitivity 
Itching and erythema on face and throat about 10 hours 
after study drug infusion. Hospitalized for evaluation 
 
and treatment.  Found to be due to 
carbamazepine and not study drug. 
17. 69 
Gunshot wound to 
head/Gunshot wound  
Patient died from a non-self-  inflicted gunshot wound to 
the head. 
18. 238 
Diverticulitis 
 
Developed severe abdominal pain, nausea and 
vomiting. Admitted for 2 days, treated with abx and IV 
fluids. 
19. 132 
Acute polyneuropathy  
 
 
 
 
Steroid-induced psychosis/ 
Psychotic disorder 
Admitted for acute polyneuropathy.  Symptoms began 
prior to first dose of study drug.  Treated with high dose 
steroids.  Study drug discontinued after only one dose.  
 
Patient admitted for psychosis thought to be due to 
high dose steroids used for treatment of 
polyneuropathy. 
20. 230 
Bronchitis 
 
Worsening non-productive cough.  CXR negative. 
Admitted for abx treatment and observation.  Resolved 
in 6 days. 
21. 47  
Lupus peritonitis/ Peritonitis 
lupus 
Patient admitted with pelvic pain; laparascopy normal 
except for question of hyperemia.  Differential PID vs. 
lupus peritonitis.  Final diagnosis of lupus peritonitis. 
Continued on study drug. 
22. 115 
Left ankle fracture/ankle 
fracture 
 
Patient fell and fractured ankle.  Admitted for surgery. 
Study drug interrupted for surgery. 
 
23. 66 
Hypersensitivity reaction 
to study drug infusion/Drug 
Hypersensitivity 
5 minutes into first study drug infusion patient noted 
itching on face and chest tightness.  Wheezing on 
chest exam.  Admitted for observation.  Symptoms 
resolved after cessation of infusion.  Study drug 
discontinued. 
24. 158 
Superficial gastric 
ulcer/gastric ulcer 
Haematemasis 
 
Developed hematemesis. Admitted to hospital for 
gastroscopy which revealed small ulcer.  Treated with 
proton pump inhibitor. 
25. 33  
Lupus flare/SLE 
 
 
Anxiety and 
depression/Depression 
 
Admitted for lupus flare.  Treated with pulse 
prednisolone  
 
Admitted for anxiety and depression following the death 
of patient’s brother. No further details provided. 
 

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Dehydration 
No details provided (occurred at same time as 
admission for anxiety and depression).  Patient had 
discontinued study drug just prior to this  
event. 
26. 113 
Chest pain 
 
 
 
Costochondritis 
Admitted with chest pain. Treated with pulse Solu-
Cortef.  
 
As above. 
27. 161 
Secondary 
pericarditis/Pericarditis 
 
Pleural effusion 
Patient admitted with  pleuritic chest pain.  Found to 
have pleural effusion and pericarditis.  Patient had 
already been discontinued from study drug prior to this 
event. 
28. 233 
Arthritis exacerbation/ 
Arthritis 
 
Mesangioproliferative 
Glomerulonephritis 
 
Admitted 3 days for treatment of arthritis myalgias.  
Treated with high dose prednisone.  
 
One month after treatment for arthritis, admitted with 
renal flare activity.  Biopsy revealed mesangial 
glomerulonephritis.  Discontinued from study drug and 
treated with pulse therapy and plasmapheresis. 
 
 
AEs of Special Interest: (Note, the data summarized here include the more extensive RA studies 
given the accumulation of pertinent data from those trials) 
Malignancies: The potential role of abatacept in the development of malignancies in humans is 
unknown. There was one malignancy reported in the lupus Phase II non-nephritis trial which was a 
basal cell carcinoma (5). Given the limited accumulation of risk or incidence for malignancy from the 
lupus program, data from the RA studies will be summarized (32-35). 
 
In RA studies, the incidence rates of malignancy overall, non-melanomatous skin cancers, solid 
organ, hematologic/lymphatic cancers, as well as each type of malignancy, have remained stable over 
time at a frequency of 138 of 3256 abatacept-treated patients observed during 9597 patient-years (33) 
or 1.44 per 100 patient-years.  Incidence rates per 100 patient-years were 0.74 for non-melanomatous 
skin cancer, 0.60 for solid organ malignancies and 0.14 for hematologic malignancies. The most 
frequently reported solid organ cancer was lung cancer (0.13 per 100 patient-years), and the most 
common hematologic malignancy was lymphoma (0.08 per 100 patient-years).  
 
The incidence rate did not increase for malignancies overall, by major type (nonmelanomatous skin 
cancer, solid tumors, and hematologic malignancies), or for individual tumor types in the double-blind 
and open label period compared to the double blind experience. The type and pattern of malignancies 
reported during open-label trials were similar to those reported for the double-blind experience. The 
incidence rate of observed malignancies was consistent with that expected in an age- and gender-
matched rheumatoid arthritis population.(36)  
 
Infusion-related and hypersensitivity reactions: In previous clinical studies with abatacept, pre-
medication to prevent hypersensitivity was not required. The incidence rate per 100 p-y of acute-
infusional event during ST and LT periods was 3.9. The annual incidence rate of acute-infusional 
events was elevated in the first year of exposure, decreased in the second, and then remained stable 
with increasing duration of exposure to abatacept. The 4 most common events contributing to this 
incidence rate per 100 p-y were dizziness (0.67), headache (0.66),hypertension (0.61), and nausea 
(0.38). The frequencies of these 4 events were 1.9%,1.8%, 1.7%, and 1.1%, respectively. Greater 
than 95% of all subjects with acute infusional events in the ST, LT, and cumulative ST and LT periods 
had events that were mild or moderate in intensity.  

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Two acute-infusional events (chest pain and anaphylactic reaction) during the LT period were 
considered serious. These 2 events resolved with treatment without clinical sequelae although drug 
was discontinued for the subject with the anaphylactic reaction (33). The incidence rate of peri- 
 
infusional event during the cumulative ST and LT period was11.21 per 100 p-y. The annual incidence 
rate of acute-infusional events was elevated in the first year of exposure, decreased in the second, 
and then remained stable with increasing duration of exposure to abatacept. Limited conclusions 
should be drawn from the numerical increase in incidence rates for some events at greater years due 
to the small number of subjects (33).  
 
The occurrence of anaphylaxis remained rare between the double blind and LT open label 
experience. Hypersensitivity was reported uncommonly. Other events potentially associated with drug 
hypersensitivity, such as hypotension, urticaria, and dyspnea, which occurred within 24 hours of 
abatacept infusion, were uncommon (33).  
 
Abatacept and Pregnancy Limited clinical experience with 102 pregnancies in patients using 
abatacept (37) (as of Dec 2010), included no reports of skeletal abnormalities. The outcomes for 
these 102pregnancy reports were as follows: outcome unknown (36), normal newborn 
(31),spontaneous abortion (14), abortion late (1), induced abortion (12), live birth (6),premature baby 
with medical problems (1), and missed abortion (1). To date, data regarding lactating women with the 
use of abatacept has not been reported. Five abatacept-exposed pregnancies have been included in 
the pregnancy registry (1pending outcome); two malformations have been reported (1 woman had a 
baby diagnosed with pyloric stenosis requiring surgery and 1 woman delivered a baby with cleft lip 
and palate). Two pregnancies have been reported in IM101045B: 1 miscarriage and 1 live birth. 
 
Safety Experience with SC abatacept (Data From Patients with RA) 
The safety experience with SC abatacept was characterized in 2 ways: events during cumulative SC 
period and events during the comparative SC/IV period. The key safety findings based on these 
analyses are listed below. (32-35).   
The cumulative SC period, during which 1879 subjects received SC abatacept for a total exposure of 
1945.60 p-y, was based on cumulative (ST/LT) pooled data of the Phase 2 and 3b studies (32). These 
data include subjects in the SC abatacept treatment group in the ST period of IM101174, subjects in 
the IV abatacept treatment group in the ST period of IM101174  (including the anti-TNF failure 
substudy) who were treated with SC abatacept in the LT period, from the start of SC abatacept in the 
LT period, subjects in ST abatacept treatment groups from IM101063, subjects in the ST placebo 
group from IM101063 who were treated with SC abatacept in the LT period, from the start of SC 
abatacept in the LT period, and subjects in IM101167, IM101173, and IM101185. No new safety 
signal was identified for SC abatacept across the parameters of death, SAEs, AEs/SAEs leading to 
discontinuation, treatment-related AE/SAEs, and overall AEs. 
 
Table 1.3.3e: 
Overall Safety for the Cumulative SC Period 
 
Number (%) of 
Subjects 
N = 1879 
Incidence Rate (per 
100 p-y) 
Poisson 95% 
Confidence Interval 
Deaths 
9 (0.5%) 
0.46 
(0.24, 0.89) 
SAEs 
161 (8.6%) 
8.63 
(7.39, 10.07) 
AEs 
1267 (67.4%) 
144.36 
(136.63, 152.53) 
AEs leading to 
46 (2.4%) 
2.37 
(1.78, 3.16) 

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Table 1.3.3e: 
Overall Safety for the Cumulative SC Period 
 
Number (%) of 
Subjects 
N = 1879 
Incidence Rate (per 
100 p-y) 
Poisson 95% 
Confidence Interval 
discontinuation 
Source: Subcutaneous abatacept summary of clinical safety. Bristol-Myers Squibb, 2010. Document Control No. 
930043734.  
Subgroup analyses by body weight did not identify differential safety profile for any of the weight 
groups, including the 24% of subjects weighing less than 60 kg. No new safety signal was identified 
for AEs of special interest: 
• 
Infection and infestation AEs were reported in 756 (40.2%) subjects with an incidence rate (per 
100 p-y of exposure) of 54.94. The majority of infections were of mild to moderate intensity. The 
cumulative SC period incidence rate of infections and infestation AEs was consistent with previous 
IV abatacept experience.  
• 
Malignancies were reported in 20 (1.1%) subjects with an incidence rate (per 100 p-y of exposure) 
of 1.04. Malignancies excluding non-melanoma skin cancer  (NMSC) were reported in 9 (0.5%) 
subjects with an incidence rate (per 100 p-y of exposure) of 0.46. The cumulative SC period 
incidence rate of malignancies was consistent with previous IV abatacept experience. 
• 
Pre-specified autoimmune events were reported in 17 (0.9%) subjects with an incidence rate (per 
100 p-y of exposure) of 0.88; most were of mild to moderate intensity with the exception of 1 
severe event (vasculitis). One pre-specified autoimmune event was reported as serious 
(sarcoidosis of moderate intensity), which led to premature discontinuation. The cumulative SC 
period incidence rate of autoimmune events was consistent with underlying disease and previous 
IV abatacept experience.  
• 
Pre-specified local injection site reactions were reported in 58 (3.1%) subjects with an incidence 
rate (per 100 p-y of exposure) of 3.09. Most local injection site reactions were of mild to moderate 
intensity; 1 event (severe injection site reaction) was serious and led to premature discontinuation. 
• 
Systemic injection reaction AEs were reported in 131 (7.0%) subjects with an incidence rate (per 
100 p-y of exposure) of 7.21. Most events were of mild to moderate intensity; none were serious; 1 
event (moderate angioedema) led to premature discontinuation.  
• 
Pre-specified acute- and peri-infusional AEs were reported in 15 (1.6%) and 35 (3.6%) subjects, 
respectively; all events were of mild to moderate intensity with the exception of 1 severe event 
(headache).  
• 
The safety profile of SC abatacept was also assessed under scenarios that might increase 
immunogenicity and determined the consequences of treating with SC abatacept (e.g., no IV load, 
monotherapy without MTX, prolonged withdrawal of therapy, switch from IV to SC abatacept).  
 
Overall, consistent safety profiles were observed for the SC abatacept and IV abatacept groups 
in rheumatoid arthritis across the parameters of death, SAEs, AEs/SAEs leading to 
discontinuation, treatment-related AE/SAEs, and overall AEs (Table 1.3.3f).  
Table 1.3.3f: 
Overall Safety for the Comparative SC/IV Population - 
IM101174 (short-term Period) 
 
Number (%) of Subjects 
 
SC Abatacept  
IV Abatacept 

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Table 1.3.3f: 
Overall Safety for the Comparative SC/IV Population - 
IM101174 (short-term Period) 
 
Number (%) of Subjects 
N = 736 
N = 721 
Deaths 
2 (0.3%) 
5 (0.7%) 
SAEs 
31 (4.2%) 
35 (4.9%) 
AEs 
493 (67.0%) 
470 (65.2%) 
AEs leading to discontinuation 
15 (2.0%) 
25 (3.5%) 
Source: Subcutaneous Abatacept Summary of Clinical Safety. Bristol-Myers Squibb, 2010. Document Control No. 
930043734. 
 
 
 
The subgroup analyses by body weight did not identify differential safety profile for any of the weight 
groups, including the 24% of subjects weighing less than 60 kg indicating that the higher exposures 
(Cmin) due to the fixed dosing regimen did not result in any additional safety risks.  
 
The safety profiles observed for SC abatacept and IV abatacept were consistent for AEs of special 
interest: 
 
• 
Infection and infestation AEs were reported in 234 (31.8%) and 221 (30.7%) subjects in the SC 
abatacept and IV abatacept groups, respectively. The majority of infections were of mild to 
moderate intensity.  
• 
Malignancies were reported in 3 (0.4%) and 5 (0.7%) subjects in the SC abatacept and IV 
abatacept groups, respectively. Of these, 2 malignancies from each group were non-melanoma 
skin cancers (NMSC).  
• 
Pre-specified autoimmune events were reported in 7 (1.0%) and 6 (0.8%) subjects in the SC 
abatacept and IV abatacept groups, respectively; all events were of mild to moderate intensity.  
• 
Pre-specified local injection site reactions were reported in 19 (2.6%) and 18 (2.5%) subjects in 
the SC abatacept and IV abatacept (i.e., SC placebo) groups, respectively. All pre-specified local 
injection site reactions were of mild to moderate intensity; none led to premature discontinuation.  
• 
Systemic injection reaction AEs were reported in 56 (7.6%) and 56 (7.8%) subjects in the SC 
abatacept and IV abatacept groups; respectively. No serious systemic injection reactions were 
reported in the SC abatacept group; 1 subject in the IV abatacept group had serious systemic 
injection reactions (nausea and headache). In both treatment groups, most pre-specified systemic 
injection reaction AEs were of mild or moderate intensity; none led to premature discontinuation.  
• 
Pre-specified acute infusional AEs were reported in 20 (2.7%) and 16 (2.2%) subjects in the SC 
abatacept and IV abatacept groups, respectively. In both treatment groups, most of the pre-
specified acute infusional events were of mild to moderate intensity; only 1 event in each 
treatment group, both reported on Day 1, led to premature discontinuation. 
 
Data from the SC abatacept clinical development program indicates that the SC abatacept formulation 
did not lead to increased immunogenicity and when present did not affect safety. 
 
1.3.3.1 Drug-Related Adverse Events 
 
As described above, the proportion of patients with SAEs in the Phase II non-nephritis lupus trial 
(population most similar to the current trial) (5) was higher in the abatacept versus placebo groups (24 

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[19.8%] vs 4 [6.8%] patients, respectively. 7 patients in the abatacept group and 2 patients in the 
placebo group had SAEs which were thought to be treatment-related (or possibly treatment-related) 
by the investigator; for abatacept: facial edema, hand edema and pyrexia in one patient and, in 
different patients alveolitis, polyneuropathy, diverticulitis, bronchitis, drug hypersensitivity and 
dehydration. In the placebo group, angioedema and lupus vasculitis occurred in one patient, and 
lupus peritonitis in one patient. Given the higher proportion of SAEs in the abatacept group, further 
post-hoc analyses were performed, which revealed that 17/24 patients with SAEs in the abatacept 
group developed the SAEs between the start of the protocol mandated burst and taper of steroids and 
Month 6 when steroids were to be tapered back to baseline. In the placebo group, 2/4 patients had 
SAEs that occurred between the start of steroid taper and Month 6 (aba paper mine) 
 
Injection Site Reactions in Adult RA Patients Treated with Subcutaneous Abatacept IM101-174 
compared the safety of abatacept including injection site reactions following subcutaneous or 
intravenous administration to patients with RA. The overall frequency of injection site reactions was 
2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous 
abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including  
 
 
hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none 
necessitated drug discontinuation. 
 
Immunogenicity in Adult RA Patients Treated with Subcutaneous Abatacept IM101-174 
compared the immunogenicity to abatacept following subcutaneous or intravenous administration. 
The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the 
subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, 
and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. 
 
Immunogenicity and Safety of Subcutaneous Abatacept Administration as Monotherapy 
without an Intravenous Loading Dose IM101-173 was conducted to determine the effect of 
monotherapy use of abatacept on immunogenicity following subcutaneous administration without an 
intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4 Ig, 
who received either subcutaneous abatacept plus methotrexate (n=51) or subcutaneous abatacept 
monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of 
treatment. The safety observed in this study was consistent with that observed in the other 
subcutaneous studies. 
 
Immunogenicity and Safety of Subcutaneous Abatacept upon Withdrawal (Three Months) and 
Restart of Treatment IM101-167 in the subcutaneous program was conducted to investigate the 
effect of withdrawal (three months) and restart of abatacept subcutaneous treatment on 
immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven 
patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized 
to either subcutaneous abatacept or placebo for the second 3-month period (withdrawal period). 
Patients from this period then received open-label abatacept treatment in the final 3-month period of 
the study (period 3).  
 
At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous abatacept 
developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous 
abatacept withdrawn during this period. Half of the patients receiving subcutaneous placebo during 
the withdrawal period received a single intravenous infusion of abatacept at the start of period 3 and 
half received intravenous placebo.  
 
At the end of period 3, when all patients again received subcutaneous abatacept, the immunogenicity 
rates were 1/38 (2.6%) in the group receiving subcutaneous abatacept throughout, and 2/73 (2.7%) in 

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the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there 
were no injection reactions, and no differences in response to therapy in patients who were withdrawn 
from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous 
therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety 
observed in this study was consistent with that observed in the other studies. 
 
1.3.4 Clinical Efficacy of Abatacept Subcutaneous Formulation 
 
The clinical efficacy of abatacept in lupus has not been tested. However, based on data from RA 
studies, there is no reason to believe that this formulation would not be equivalent to IV dosing in 
effects. The clinical development program for SC abatacept in RA included 4 Phase 3b efficacy, 
safety, and immunogenicity studies (IM101167, IM101173, IM101174 and IM101185) plus 2 clinical 
pharmacology studies (IM101013 and IM101063). Overall, the efficacy data from the SC abatacept 
development program demonstrated that the efficacy profile of SC abatacept is comparable to IV 
abatacept in patients with rheumatoid arthritis (31). This justifies the study of the SC formulation in 
SLE, based on our rationale that exploratory analysis of the IV SLE studies supports the hypothesis 
that efficacy might be demonstrated in a study in which background treatments are less aggressive 
and endpoints more discriminatory.  
 
 
 
1.4 Overall Risk/Benefit Assessment 
 
Based on the clinical trial experience in adults, the risks that may be associated with the use of 
abatacept include infections, some which may be serious or fatal, infusion related reactions, and an 
increase in respiratory adverse events and infections in patients with chronic pulmonary obstructive 
disease (COPD). Other potential risks may include the development of malignancies or autoimmune 
disorders, but an increased risk of these types of events have not been observed. As with the use of 
any protein therapeutic, antibodies against abatacept (immunogenicity) may develop. The rate of 
immunogenicity has generally been low and there has not been an apparent effect on safety, efficacy, 
or pharmacokinetics (PK).  
 
Recently a subcutaneous form of abatacept has been tested in and approved for rheumatoid arthritis. 
From substantial data testing the subcutaneous form of Abatacept in rheumatoid arthritis there is little 
reason to suspect that any novel risks should emerge to make this formulation significantly more 
problematic than the IV formulation in SLE. Data from the two lupus trials using IV abatacept  suggest 
that safety profile of abatacept in the non-nephritis lupus study IM101042 was generally similar to 
placebo, with the exception of the incidence of SAEs, which was higher in the abatacept group 
(19.8%) than that in the placebo group (6.8%), a population that is the most similar to the current one. 
These SAEs have been reviewed above, and were predominantly short hospitalizations for lupus 
flares. Of concern (and to be closely monitored in the current study) there were three nephritis flares, 
albeit none had severe biopsy manifestations (Class II, mesangioproliferative and “mild 
glomerulonephritis”) and there were three incidences of serious infections (hopefully background 
medication withdrawal will help ameliorate any combined risks for infection). Allergic/injection 
reactions will also need to be closely monitored in this study.  
 
 
Overall, in a population of lupus patients with significant unmet medical need, which develops 
significant immediate morbidity, long term disability and mortality on current standards of care, the 
risks as discussed above are reasonable and manageable through careful screening and monitoring 
and prompt attention to new medical problems. The current study, cognizant that abatacept has 
potent immune-modulating action, restricts entry to patients with significant and potentially organ-
threatening disease who are otherwise not entering the study with seriously damaged renal, liver, 

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digestive, pulmonary, cardiac or circulatory systems that might increase their risks for infections and 
other complications, which might cloud the proper assessment of safety in the population. 
 
A further consideration is that alternative treatments available to our patients are known to have high 
risks for metabolic derangements, organ toxicities and impairment of host defenses against infections 
and possibly neoplasms (2). Thus the alternative treatments, many of which have broader immune 
suppressive potential than CTLA4Ig does, are not known or expected to have a better safety profile 
than that of abatacept. Indeed with a study design that withdraws background immune suppressants, 
a possible benefit could accrue from diminished toxicity.  
 
 
1.5 RESEARCH HYPOTHESIS 
 
We hypothesize that use of a novel, simplified trial design which incorporates withdrawal of 
confounding background immune suppressants with a robust clinical efficacy endpoint, a greater 
number of patients with SLE who are randomized to abatacept will achieve the primary efficacy 
endpoint of BICLA than patients randomized to placebo.  
 
 
1.6 STUDY RATIONALE 
 
This double blind placebo controlled study will randomize  lupus patients with active arthritis to 
abatacept or placebo for a six month trial to determine which group has a greater response rate as 
measured by the primary endpoint of BICLA (BILAG based Combined Lupus Assessment ) 
(BILAG=British Isles Lupus Assessment Group index). The dose of 125 mg administered 
subcutaneously weekly has been validated in an RA population and was chosen for this study in SLE 
on the basis of the assumption that it will be equal in efficacy to intravenous infusion without adversely 
affecting the safety profile. This current small study is not designed to test that assumption, but on the 
basis of RA data it seems reasonably likely that any efficacy signal from abatacept will be detectable 
through this route of administration in SLE. Subcutaneous dosing is a more practical clinical approach 
in the management of patients overall, is much easier for the patients, and will lessen the costs of an 
investigator initiated study while being unlikely to negatively affect either patient safety or the 
information that can be obtained. 
 
The rationale for this study design, which is based on exploratory analysis of previous abatacept and 
other lupus studies, is to provide a more discriminatory protocol and a more robust endpoint than was 
available in prior trials for lupus.  A further rationale is to provide proof of concept for the general 
feasibility of smaller pre-Phase III trials in SLE with greater potential effect size than has been 
possible in the past and ability to make confident go/no go decisions for Phase III development after 
less investment of time, patient risk, and expense than is usual in Classic Phase II designs.  
 
Indeed this project is specifically powered (based on data about placebo group response rates from 
our BOLD study, a prior, similar study) to support a rational decision about further development of 
abatacept for SLE.  
 
 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective: To compare response rates between Abatacept-Treated and Placebo-
Treated Patients with active lupus arthritis in a trial designed with background immune suppressant 

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withdrawal, limited steroid rescue, and a robust, discriminatory endpoint. Statistical powering is based 
on this primary objective. 
 
2.2 Secondary Objectives: Secondary clinical endpoints will include: SRI 4/5, changes in joint 
counts, SLEDAI, BILAG, CLASI, PGA, and DIAL measures. We will also Integrate biologic discovery 
into the clinical trial to support both pre-specified and exploratory biomarker discovery. Data will be 
generated that might be used to help select more appropriate patient subsets for future trials and to 
guide optimal dosing strategies. Optimizing patient selection and dosing are important goals for 
further increasing demonstrable effect size in trials by increasing the response rates in the treatment 
group.  
 
Optimizing patient selection and dosing are important goals for further increasing effect size in trials. 
In fact, the two Aims of this project are co-dependent, since each increases the likelihood of 
interpretable data and could have high impact on increased effect size for an effective product. Also, 
Aim 2 would be less feasible without the strategy of Aim 1 to decrease the cacophony of background 
medications, which have clouded interpretation of many treatments for SLE in the past.  
 
 

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Ethical Considerations:  
 
Integration of biologic discovery into clinical trials will generate data that might be used to help select 
more appropriate patient subsets for future trials and future treatment in clinic and to guide optimal 
dosing strategies. This is an ethical consideration since it could decrease the numbers of patients 
inappropriately exposed to a study medication in trials and in practice, and by allowing a better 
delineation of efficacy in the right population(s) this could also decrease the likelihood of widespread 
exposure in Phase III trials prior to acquiring sufficient data supporting potential efficacy.  
 
The ethical basis of the current trial design has been debated widely in the lupus community. There is 
a realistic concern that withdrawal of background therapy will increase the risk of lupus flares and this 
trial design would be inappropriate for very ill patients such as those with active nephritis. However by 
decreasing the continued use of background immune suppressants which were obviously not working 
at the time of entry, by allowing steroid rescue and even restarting of meds as needed during the trial 
(defining such patients as non-responders) this design could be argued to be far more ethical than 
trials which legislate continuance of inadequate and potentially toxic background immune suppressant 
treatments for an entire year, with probable increase in risk for infections. In such protocols, patients 
who do not improve have only the choice of minimal rescue steroids or to drop out of the study, 
leading to unnecessary suffering which will not be required in this trial design. Finally, the concern 
about increasing flare risk should be somewhat alleviated by the results of the MMF, BOLD and 
Rontalizumab studies (all three of which have been completed using this trial design, and the latter 
presented at ACR 2012 (39)  
 
3.1 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50). 
 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and the 
subject informed consent will receive Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approval/favorable opinion before initiation of the study. 
 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity of 
the subjects of the study or the scientific value of the study. 
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study personnel 
where sanctions have been invoked or where there has been scientific misconduct or fraud (eg, loss 
of medical licensure; debarment).  
 
3.2  Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion from 
the IRB/IEC for the protocol, the informed consent form, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator should 
also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling information to be 

ABC Trial – Version 1/08/2016 
 
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provided to subjects, and any updates, as well as descriptions of ancillary pharmacokinetic and 
pharmaco-dynamics studies.  
 
The investigator should provide the IRB/IEC with reports, updates, and other information (eg, 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
3.3 Informed Consent 
Investigators must ensure that subjects or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
Investigators must: 
 
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study. 
 
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion.  
 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form and 
any other information to be provided to the subjects, prior to the beginning of the study, and after 
any revisions are completed for new information. 
 
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the subject. 
 
6) Revise the informed consent whenever new information is available relevant to the subject's 
consent. The investigator, or a designee should fully inform the subject or the subject's legally 
acceptable representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. This 
communication should be documented.  
 
Minors (subjects under 18) or subjects unable to give informed consent will not be included in this 
study. The rights, safety, and well-being of the study subjects are the most important considerations 
and should prevail over interests of science and society. 
 
 

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4       INVESTIGATIONAL PLAN 
 
4.1   Study Design and Duration 
 
Planned Study Design: This will be a randomized, double blind, placebo-controlled trial of patients 
with active SLE who must have active arthritis (at least BILAG B and at least 3 tender and 3 swollen 
joints) at the screening visit. Randomization to placebo vs abatacept will be performed on a 1:1 
scheme by an unblinded pharmacy technician who will have no contact with study subjects. Patients 
will give weekly subcutaneous injections of study drug at home except for the first dose which they will 
give in clinic under the supervision of a nurse/coordinator.  
 
 
 
Subjects will be evaluated monthly by an investigator/subinvestigator who are required to have 
passed LFA testing for Hybrid SLEDAI, BILAG 2004 and CLASI. Additional assays will be PROs 
(Lupus PRO and SF36) and the DIAL endpoint (endpoints are defined below and case report forms 
for each endpoint can be found in Appendices). The primary endpoint will be measured at 6 months. 
This will be a comparison of response rates by the BICLA (BILAG-based Combined Lupus 
Assessment) which is a scoring system incorporating several measures. Improvement must be 
documented using the BILAG (British Isles Lupus Assessment Group) index, with no worsening in any 
organ by BILAG or SLEDAI (SLE Disease Activity Index) and less than 10% worsening in PGA 
(Physicians Global Assessment) as well as no initiation of off protocol immune suppressants or 
steroids.  
 
Secondary endpoints will include changes in each of the above mentioned single outcome measures, 
CLASI, and assessment of patient reported outcomes (secondary endpoints are further described 
below). Biomarker evaluations with a specific focus on T Cell subset pathways and B Cell pathways 
will also be explored in  a responder analysis.  
 
Screening procedures: At the screening visit, patients who are known to have 4 ACR classification 
criteria (1997 revised) for SLE who present with active arthritis (a minimum of 3 swollen and 3 tender 
joints) will be invited to undertake screening procedures unless an exclusionary criteria is already 
known. Screening procedures will begin with the informed consent process during which patients will 
review the complete informed consent information as approved by the IRB, which will include a full 
description of the study and the procedures involved, patients’ rights and responsibilities, and 
alternative treatments that are available if the patient does not decide to participate in the study.  
 
Subjects will have a chance to have their questions answered prior to making a decision. Once the 
informed consent procedures are completed, the following will be completed: medical history, physical 
examination, review of inclusion and exclusion criteria (some of which will require awaiting blood test 
results), EKG, PRO measures filled out by the participant (Lupus PRO and SF-36), and clinician 
measures (SLEDAI, BILAG 2004, CLASI, DIAL, PGA).  
 
To the extent that a history and physical examination was already performed by one of the 
investigators that day in the course of routine medical care they will not need to be repeated. 
Screening blood tests will be drawn (maximum 160 cc) including baseline PK and PD samples, and 
arrangements will be made to contact the patient for the first dosing visit or (if is determined the 
subject is ineligible) a visit to discuss alternative care. Patients who donate blood at screening for PK 
and PD and who are later deemed ineligible for the trial will be told, as part of the informed consent 
process, that these samples may be used for various analyses. Patients retain the right to withdraw 

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permission for the use of their blood samples at any time. Screening procedures can be performed on 
the same day the informed consent is signed or any other time up to and including the baseline visit 
(the screening period) as long as full eligibility is established at the time of randomization.  
 
The study population will include patients between the ages of 18 and 70 who meet a minimum of 4 
1997 revised ACR criteria for SLE and who present with a minimum of 3 tender and 3 swollen joints 
attributable to lupus arthritis. Patients may have other active manifest 
ations of SLE, and, in the opinion of the investigator, they must be sick enough for intention to treat 
with a biologic and stable enough for this trial design, which includes withdrawal of any background 
immune suppressants, to be appropriate. 
 
This study will enroll patients until 60 have completed the protocol through at least the six month 
point. Randomization will be 1:1 to abatacept or placebo. Approximately 30 patients are expected to 
complete each arm. At each visit history, physical, and blood tests appropriate to complete the 
outcome measures will be performed, and adverse event reporting and medication updates will be 
performed.  
 
Subjects may continue to take nonsteroidal anti-inflammatory medications (including prn NSAIDS) 
and up to 20 mg prednisone (or oral steroid equivalent) daily during the study although steroids will be 
tapered as tolerated. If the patient is taking an immune suppressant (e.g. antimalarials, 
mycophenolate mofetil, azathioprine, leflunomide, methotrexate, a calcineurin inhibitor or belimumab) 
at screening, this must be stopped prior to or on the day of the baseline visit. Patients can elect to 
receive one or more depomedrol injection(s) up to a total of 320 mg total at the time of the screening 
visit and/or up to and including the Month 2 visit. Daily oral steroids will be tapered as tolerated if and 
when the patient begins to improve. 
 
Subjects will be encouraged to avoid off protocol medications if possible, but if off protocol 
medications are given, the patient may, at the discretion of the investigator continue in the protocol as 
a designated “non-responder”, and continue to be followed at monthly visits until the subjects reaches 
Month 6. Furthermore, patients may elect to receive open label abatacept as early as Month 3 (three 
Months after the first Dosing Visit) if their disease activity is not improved at that visit compared to 
baseline. Such subjects will also be designated as non-responders for the primary endpoint at Month 
6. For those patients taking daily oral steroids at screening, they will be encouraged to taper these as 
tolerated if and when they begin to improve. Patients who withdraw from the protocol for any reason 
will be encouraged to come for safety follow up visits 2 and 4 months after the last study visit. 
 
The primary endpoint will be determined at six months, but all patients can then choose to receive 
open label abatacept for an additional six months. Maximal duration of treatment will be 12 months. 
There will be two follow up visits two and four months after the end of study. However, patients who 
withdraw after six months will be considered completers of the primary study in the amassing of 60 
completers. The criteria for evaluation will be improvement (without worsening) in signs, symptoms 
and diagnostic results as defined by the BICLA (primary endpoint). Additionally joint counts, the SRI 
4/5, hybrid SLEDAI, BILAG 2004, CLASI, DIAL, Lupus PRO and SF-36 will be evaluated. 
 
After receiving the first injection in clinic, patients will administer the study medication at home. 
Subjects will return to the clinic monthly for six months, and those who continue will be evaluated 
every 4weeks for the second six months. There will be two follow up visits at two month intervals after 
the end of study for each patient. Visits at which maximal blood samples are taken due to PD 
scheduling are Screening, and Months 3, 6, 9 and 12 (up to 160 cc). At all other visits no more than 
80 cc maximally can be drawn.  
 
Please refer to the Time and Events Schedule for a grid of procedures.  
 
 

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4.2 Study Population: For entry into the study, the following criteria MUST 
be met. 
 
4.2.1 Inclusion Criteria 
 
1) Signed Written Informed Consent Before any study procedures are performed, subjects will have 
the details of the study described to them, and they will be given a written informed consent document 
to read. Their questions will be answered. Then, if subjects consent to participate in the study, they 
will indicate that consent by signing and dating the informed consent document in the presence of 
study personnel. 
2) Target Population:  
     Patients with at least 4 1997 revised ACR classification criteria for SLE  
     Active polyarticular arthritis with a minimum of 3 tender and 3 swollen joints observed at the 
screening visit and a history consistent with BILAG 2004 “B” arthritis  
 
3) Age and Reproductive Status 
 
Age: Men and women 18 to 70 years of age.  
 
Reproductive Status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP 
comprises women who have experienced menarche and who have not undergone successful 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are 
not post-menopausal (see definition below) 
Post-menopause is defined as:  
i. Women who have had amenorrhea for  12 consecutive months (without 
another cause) 
ii. Women who have irregular menstrual periods and a documented serum FSH 
level > 35 mIU/mL. 
iii. Women who are taking hormone replacement therapy (HRT). 
 
The following women are WOCBP: 
iv. Women using the following methods to prevent pregnancy: Oral contraceptives, 
other hormonal contraceptives (vaginal products, skin patches, or implanted or 
injectable products), or mechanical products such as intrauterine devices or 
barrier methods (diaphragm, condoms, spermicides). 
v. Women who are practicing abstinence. 
vi. Women who have a partner who is sterile (eg, due to vasectomy). 
 
WOCBP and sexually active men with WOCBP partners must use contraception throughout the 
study and for up to 10 weeks after the last dose of study drug. This will be discussed with each 
subject individually and the plan documented. WOCBP must have a negative urine pregnancy test 
result (minimum sensitivity 25 IU/L) within 0 to 48 hours before the first dose of study drug and at all 
subsequent visits. Women must not be breast-feeding.  
 
 

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4.2.2 Exclusion Criteria 
 
Target Disease Exceptions Patients with acute nephritis requiring induction therapy, CNS lupus 
(except chorea, cranial neuropathy, and resolving optic neuritis) or any lupus condition requiring 
cyclophosphamide, biologics, or IV bolus steroids of >/= 500 mg. 
 
1) Medical History and Concurrent Diseases 
a. Subjects who are incapable of understanding or completing study-related assessments. 
b. Subjects with any condition, whether or not related to SLE, which, in the opinion of the 
investigator, might place a subject at unacceptable risk for participation in the study. 
c. Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers 
cured by local resection or carcinoma in situ.  
d. Subjects who currently abuse drugs or alcohol. 
e. Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months before 
the informed consent document was signed. 
f. Subjects who have received any live vaccines within 3 months of the anticipated first dose of 
study medication. 
g. Subjects with any serious bacterial infection within the last 3 months, unless treated and 
resolved with antibiotics, or any chronic bacterial infection (eg, chronic pyelonephritis, 
osteomyelitis, or bronchiectasis). 
h. Subjects at risk for tuberculosis (TB). Subjects with active TB within 3 years, even if treated; 
history of active TB > 3 years ago, unless documented prior anti-TB treatment appropriate in 
duration and type; current known or suspected active TB; and latent TB not successfully treated (≥ 
4 weeks at baseline).  
 
2) Physical and Laboratory Test Findings 
a) Subjects must not be known to be positive for hepatitis B surface antigen. 
b) Subjects who are known to be positive for hepatitis C antibody may participate if the presence 
of hepatitis C virus can be excluded by polymerase chain reaction or recombinant immunoblot 
assay at screening.  
c) Subjects with any of the following laboratory values 
i) Acute hemolytic anemia with hemoglobin < 7.0 g/dL or known change in Hg by 2.0 g/dL 
within the last four months unless due to SLE and stable for the past month 
ii) WBC < 2500/mm3 (< 2.5 x 109/L) unless due to chronic lupus activity and stable for the 
past month 
iii) Platelets < 40,000/mm3 (< 3 x 109/L) (If less than 100,000 must have been stable (within a 
range of 10,000/mm3 ) either by historical testing of known chronic thrombocytopenic 
patients within two months of screening or in two tests during the screening period at least 
one week apart. 
iv) Serum creatinine > 2 times the ULN 
v) Serum ALT or AST > 2.5 times the ULN 
d) Any other laboratory test results that, in the opinion of the investigator, might place a subject at 
unacceptable risk for participation in the study. 
 
 

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4) Allergies and Adverse Drug Reactions: Known allergy or adverse sensitivity to any  
     components of the study agent or carrier. 
5) Sex and Reproductive Status: See Section on WOCBP (Section 4.2.1, item # 3.) 
 
6) Prohibited Treatments and/or Therapies 
a) Subjects who have at any time received treatment with any investigational drug within 28 days 
(or less than 5 terminal half-lives of elimination) of the Day 1 dose.   
b) Subjects who have received cyclophosphamide within 3 months of the Day 1 dose or bolus 
parenteral steroids >/= 500 mg within 1 month of screening. 
c) Ongoing treatment (after the baseline visit) with immune suppressants (such as antimalarials, 
methotrexate, azathioprine, mycophenolate mofetil, leflunomide, calcineurin inhibitors or 
belimumab) after the baseline visit. These may be stopped or tapered as soon as informed 
consent procedures have been completed at the screening visit.  
d) Prednisone > 20 mg po qd at the time of the screening visit (steroids will additionally be 
tapered during the study if possible at the discretion of the investigator). The exception to this 
are the protocol-allowed Depomedrol shots which will be used for rescue if needed. A total of 
320 mg of intramuscular depomedrol can be given in increments of 40-160 mg at any time 
from the Screening Visit (after informed consent is signed and blood drawn) until the end of 
the Month 2 Visit (after blood drawn) If subjects remain on prednisone, no dose increases will 
be allowed during the study. 
 
Other Exclusion Criteria 
• 
Prisoners or subjects who are involuntarily incarcerated. 
• 
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, 
infectious disease) illness. 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria. 
 
4.2.3 Discontinuation of Subjects from Treatment: Subjects MUST discontinue 
investigational product for any of the following reasons: 
 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• 
Any clinical adverse event, laboratory abnormality, or intercurrent illness which, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best interest of the 
subject. 
• 
Pregnancy: WOCBP will be instructed to contact the investigator or study staff if 
they suspect they might be pregnant (eg, missed/late menstrual period) at any time during study. 
Urine pregnancy tests will be performed at each monthly visit as well. The investigator will 
immediately notify BMS if a study subject becomes pregnant. 
• 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical illness. 
 
All subjects who discontinue should comply with protocol-specified follow-up procedures outlined in 
Section 6. This will entail monthly visits if subjects discontinue treatment prior to month 6, and  then a 
visit 2 months after withdrawal and an additional visit four months after withdrawal at which safety and 
efficacy evaluations will be performed the same as the Month 6 visit. The only exception to this is 
when a subject withdraws consent or loses the ability to consent freely  
 

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(ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness). If a subject withdraws before completing the study, the reason for withdrawal must be  
 
documented appropriately. The second six months of open label therapy are optional. Patients will be 
determined to complete the protocol if they complete Month 6 and two follow up visits. Patients will be 
considered evaluable for the primary endpoint if they complete Month 6. Patients lost to follow up 
before Month 6 will be considered non-responders. 
 
5. Treatments 
 
5.1 Study Treatment: Abatacept:  
 
Definition of Investigational Product: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information about the 
authorized form. In this protocol, the investigational product is abatacept.  
 
Definition of Non-Investigational Product: Other medications used in the study as support or 
escape medication for preventative, diagnostic, or therapeutic reasons as components of a given 
standard of care. In this protocol, the non-investigational products are optional depomedrol 40-160 mg 
intramuscular shots given prn (only if needed) at screening, baseline, or at Months 1 and/or 2. No 
more than 320 mg total may be given before/at Visit 2.  
 
5.1.1 Identification 
 
Abatacept Injection, 125 mg/Syringe (125 mg/mL), is a sterile solution for SC administration, which 
contains approximately 126 mg abatacept, 171 mg sucrose, 8 mg Poloxamer 188, 0.28 mg 
monobasic sodium phosphate, monohydrate, and 0.84 mg dibasic sodium phosphate, anhydrous, in 
Water for Injection. It is packaged in 1 mL long glass syringe barrel staked with a 29 gauge stainless 
steel needle and stoppered with a 7.1 mm rubber stopper. The composition of this solution has a ratio 
of monobasic sodium phosphate, monohydrate, and dibasic sodium phosphate, anhydrous, used to 
achieve the target pH of 7.2. It appears clear to slightly opalescent, colorless to pale yellow solution, 
essentially free of particulate matter on visual inspection.  
 
5.1.2 Packaging and Labeling 
 
Abatacept SC is known to be supplied in a box of 4 syringes with an open-label. We will require 
abatacept SC and placebo suitable for the unblinded pharmacist to prepare and dispense in syringes 
appropriate to maintain the blind.  
 
5.1.3 Handling and Dispensing 
 
The investigational product should be stored in a secure area according to local regulations.  At the 
OMRF we have a locked pharmacy, an experienced clinical trials pharmacy technician who is on site 
full time, and appropriate storage conditions for a range of investigational products. An inventory will 
be kept by the unblended pharmacy technician to ensure that the blinded study medication is 
dispensed only to authorized study personnel (the coordinator) to ensure that it is given only to the 
appropriate study subjects. 
 

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The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity), as described below. This task 
will be delegated to our well trained pharmacy technician who will be monitored by an outside  
 
 
 
 
pharmacist from the University of Oklahoma to ensure ongoing completeness of inventory, 
temperature logs, assignment logs, chain of custody documentation, and regulatory records. 
Abatacept SC formulations (prefilled syringes) and corresponding placebo will be stored under 
refrigeration (approximately 2 to 8°C) and protected from long-term (more than 24 hours) exposure to 
light. Temperature logs will ensure stability of temperature and prevention of freezing. Abatacept 
injection, 125 mg/syringe (125 mg/mL) and placebo for SC administration are ready to use solutions 
provided in pre-filled siliconized syringes with a 29 gauge needle. Care will be taken when handling 
the injectable drug products that are used in this protocol. Proper aseptic techniques must be used 
when preparing and administering sterile parenteral products such as abatacept. Parenteral drug 
products should be inspected visually for particulate matter prior to administration. If concerns 
regarding the quality or appearance of the investigational product arise, it will not be dispensed and  
BMS will be contacted immediately. 
 
5.2 Drug Ordering and Accountability 
 
 
5.2.1 Initial Orders 
 
The site will request initial shipment with a Drug Request Form. The unblinded pharmacy technician 
will provide at least weekly reports of inventory use or more frequently if needed to maintain inventory. 
 
5.2.2 Re-Supply 
 
All resupply requests will be initiated by the site by completion of the Drug Request Form. 
 
5.3 Method of Assigning Subjects to a Treatment 
 
There will be no stratification in this protocol. Patients will be randomized 1:1 to treatment or placebo 
from Month 1-4. At month 3 patients who are flaring or have not improved despite availability of 
steroid rescue protocols will be allowed to choose open label Abatacept from Month 4 onwards, 
however they will be considered non responders at Month 6. From Month 6 onwards, all patients will 
receive the option to continue in the study and open label Abatacept until Month 12. Patients will 
continue to be followed Monthly until Month 12 with follow up visits at Months 14 and 16.  
 
5.4 Selection and Timing of Dose for Each Subject 
 
Patients will be randomized in a 1:1 scheme to receive abatacept at recommended dosing or placebo. 
The recommended dosage is 125 mg/mL single-dose prefilled glass syringe for subcutaneous 
injection. Patients will give themselves the first injection in clinic under the supervision of  the study 
nurse and will self-inject at home thereafter on a weekly basis. If desired a family member can give 
the injection but must come to the clinic to be supervised by the nurse at the first dose.   
 
5.4.1 Dose Modifications 
 

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Immune suppressants will be stopped on or before baseline. Patients will be encouraged to taper any 
daily oral steroids as tolerated, if and when they begin to improve. Dose increases of oral steroids will 
not be allowed. No specific changes in dosing of abatacept are part of the protocol, however study 
medication may be held for one visit once (maximum) during the first 6 months in the protocol due to 
medical decision or extenuating circumstances, however open label study medication can be withheld 
at any time at the discretion of the investigator. 
 
5.5 Blinding/Unblinding  
 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical emergency 
or pregnancy in a subject, in which knowledge of the investigational product is critical to the subject's 
management, the blind for that subject may be broken. Before breaking the blind of an individual 
subject’s treatment, the investigator should have determined that the information is necessary, ie, that 
it will alter the subject’s immediate management. In many cases, particularly when the emergency is 
not investigational product-related, the problem may be properly managed by assuming that the  
 
subject is receiving active product without the need for unblinding. The BMS Bioanalytical Science 
representatives and contract resource organizations performing the testing will be unblinded to the 
randomized treatment assignments in order to minimize unnecessary analysis of PK and 
immunogenicity samples from the placebo group of subjects. 
 
5.6 Concomitant Treatments 
 
5.6.1 Prohibited and/or Restricted Treatments 
 
See Exclusion Criteria for limitations to treatments that may have been taken prior to entry into the 
protocol. During the protocol, immune suppressants will be withdrawn at or before the baseline visit 
(with optional steroid rescue therapy as described in the main body of the protocol) and will not be 
restarted unless the patient flares at or after Month 3 or earlier to a degree that the protocol-allowed 
steroid injection is not considered appropriate. Initiation of immune suppressant medication at that 
point would not be considered a protocol violation, but may dictate non-responder status during the 
rest of the trial.  However, should a patient develop a degree of flare which, in the opinion of the 
investigator is inappropriate for continuing the protocol, this will be counted as non-response and the 
patient must be withdrawn from the protocol and study treatment stopped. 
 
 
5.6.2 Other Restrictions and Precautions 
 
SLE is a complicated disease and it is sometimes difficult to determine if acute illness is caused by 
infection, lupus disease, or medication side effects. For this reason, supervision of the study clinic by 
a physician experienced in the care of lupus patients is imperative. Five such physicians will be 
available to follow the patients in this study, Drs. Merrill, Chakravarty, James, , Arriens and Thanou, 
as well as Joe Rawdon, DNP, APRN. Adverse events will be reported to the IRB and reviewed by the 
DSMB as described elsewhere in this protocol.  
 
 
5.7 Treatment Compliance 
 
After the first injection, patients will self-administer injections at home and will keep a diary to record 
date and time of each injection. They will be asked to return the used syringes to the clinic at each 

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visit. They will be questioned at each visit about problems with administration and/or degree of 
compliance that has been possible. These records will be kept as part of the study records so that 
overall compliance in the treatment vs placebo group can be estimated. 
 
6. STUDY ASSESSMENTS AND PROCEDURES 
 
6.1 Time and Events Schedule 
 
Qualified subjects who meet screening criteria will return to the clinic within one month for 
randomization (Treatment Visit 1). Because study treatments are weekly, window for dosing shall be 
±3 days. 
 
All visits include sufficient history, physical examination, and diagnostic testing to meet the 
requirements for scoring the SLEDAI and BILAG. Because of this they are all adequate for performing 
a complete safety and well-being assessment. Therefore no specific new procedures will be specified 
for either end of study or safety follow up visits. Interim visits for adverse events will be performed as 
clinically warranted. The reason for any early withdrawal/study drug discontinuation will be 
documented. Patients are referred to our research cohort from throughout Oklahoma and surrounding 
states. 
 
 

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TIME AND EVENTS SCHEDULE: PROTOCOL IM101-345  
 
Procedure 
Screening 
Visit 
Treatment 
Visit 1  
1st Dosing 
Treatment 
Visit 2-7 
Month 1-6 
Follow 
up 
Visits  
post-Rx 
Visits 8-
13 
Month 7-
12 
Eligibility Assessments 
 
 
 
 
 
Informed Consent  
X* 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Medical History 
X 
X 
X 
X 
X 
Safety Assessments 
 
 
 
 
 
Medication List 
X 
X 
X 
X 
X 
History, Vital Signs, Physical Examination 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
X 
X 
X 
Clinical Laboratory Tests 
X 
X 
X 
X 
X 
PK sampling 
X** 
X** 
X** 
 
X** 
Immunogenicity 
X*** 
X*** 
X*** 
 
X*** 
PD sampling 
X**** 
X**** 
X**** 
 
X**** 
Pregnancy Test 
X 
X 
X 
X 
X              
Efficacy Assessments 
 
 
 
 
 
SLEDAI/SSFI/PGA 
X 
X 
X 
X 
X 
BILAG 2004 
X 
X 
X 
X 
X 
CLASI 
X 
X 
X 
X 
X 
DIAL 
X 
X 
X 
X 
X 
Patient Questionnaires  
(SF-36, LupusPRO) 
X 
X 
X 
X 
X 
Clinical Drug Supplies 
 
 
 
 
 
Randomize 
 
X 
 
 
 
Dispense Study Treatment baseline and q 
month 
 
X 
X 
 
X 
 
 
 
 
 
 
*Repeated for protocol amendments or new safety data  
** Screening, Months 1,2, 3,4, 6,  7,8, and 12 and/or EOS (if patients withdraw early) 
***Screening, Months 1,2, 6, 7, 8, 12 and/or EOS 
**** At Screening Visit, first dosing, visits 3, 6, 9 and 12 and/or EOS (</= 160 cc blood, up to 30cc urine, up to 10cc saliva)  
 
Non PD visits are restricted  to </= 80 cc blood, up to 30 cc urine, up to 10 cc saliva) 
Note that PK/PI/PD labs at screening should be drawn at the screening visit if possible, otherwise may be drawn anytime up to  
and including the First Dosing Visit, but must be draw prior to receiving any steroid injection(s) in the protocol.  
 

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46 
 
 
 
6.2 Study Materials Bristol-Myers Squibb (BMS) will provide abatacept subcutaneous 
formulation at no cost for this study. 
 
6.3 Safety Assessments All subjects who receive a dose of abatacept will be evaluated for 
safety. Safety outcomes include adverse events, clinically significant changes in vital signs, laboratory 
test abnormalities, and tolerability of the drug. The investigator will determine the severity of each 
adverse event as mild, moderate, severe, or very severe. Reference will be made to the National 
Cancer Institute Common Terminology Criteria for Adverse Events. Laboratory findings that the 
investigator rates as clinically significant will be recorded as adverse events. The investigator will 
determine the relationship of the adverse event to the study drug. Any occurrence of a SAE from time 
of consent forward, up to and including follow-up visits will be reported. See Section 7.3.1 for the SAE 
reporting procedures. 
 
6.3.1 Physical Examinations 
Physical examinations will be performed at every visit, suitable to assess patient safety and to perform 
the efficacy evaluations which are multisystem indices (see below) 
 
6.3.2 Breast and Hematologic Cancer Screening 
Patients with SLE have a slightly decreased risk for breast cancer compared to healthy controls and a 
slightly increased risk for lymphoma. Appropriate general cancer screening procedures will be 
discussed with each patient entering the study. Female subjects who are greater than 50 years of age 
will have a manual breast examination performed at the screening visit and all subjects will be 
examined for lymphadenopathy. Subjects having a cancer screening that is suspicious for malignancy 
will have drug administration withheld until the possibility of malignancy can be reasonably excluded 
following additional clinical, laboratory or other diagnostic evaluations. The screening period may be 
extended under such circumstances at the discretion of the investigator.  
 
 
6.4 Efficacy Assessments 
The efficacy assessments that have been documented in the Time and Events Schedule are 
described below. Case report forms are included in the Appendices. 
 
 
6.4.1 Primary Efficacy Assessment: BICLA Response 
 
BICLA stands for BILAG-based Combined Lupus Assessment. The BILAG refers to the British Islese 
Lupus Assessment Group Index. We will be using the version known as BILAG 2004 (37).This 
consists of 97 descriptors for signs and symptoms of lupus divided into 9 organ systems (see 
appendices for case report forms). Each organ system receives a rating of A (severe disease activity), 
B (moderate disease activity) C (mild disease activity) D (no disease activity in an organ previously 
affected) or E (organ inactive and never previously active). These ratings are derived from 
assessments made on each descriptor within each organ and the determination of whether activity is 
not present, improving, same, worsening or new/recurrent when comparing the degree of disease 
activity during the past month to the previous month.  
 
The BICLA (8) includes scores from the BILAG, the SLEDAI and the PGA. The SLEDAI which will be 
used is the hybrid SLEDAI which incorporates components of two SLEDAI versions, the SLEDAI 2K 
and the SELENA SLEDAI which was devised for the Safety of Estrogens in Lupus Erythematosus 

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National Assessment (SELENA) trial. The PGA refers to Physician’s Global Assessment which is 
performed on a weighted 100 mm scale devised specifically for lupus designed as part of the SSFI 
(SELENA SLEDAI flare index). Based on the BILAG scores at entry (A-E in each organ) the BICLA 
response is defined by at least one letter grade improvement in each organ without an increase in the 
SLEDAI score or an increase of 10% in the PGA. There must also be no off-protocol treatment in 
order to meet this response criteria. The primary endpoint is BICLA response rates at month 6 in the 
abatacept treatment group vs the placebo group.  BICLA response at each month will also be 
assessed as a secondary endpoint. 
 
6.4.2 Secondary Efficacy Assessments  
 
All of the individual components of the BICLA will be assessed in different ways as secondary 
endpoints. These will include: 
 
1. BICLA response at each month 
2. SRI 4 and 5: Response is defined at an endpoint date (EOS and each month vs baseline) The SRI 
endpoint (7) is defined as a 4 (or 5) point drop in SLEDAI compared to baseline without and increase 
in BILAG or 10% worsening by PGA. 
3. Tender and swollen joint counts (to be analyzed separately and as composite score) 
4. Change in SLEDAI scores (EOS and each month vs baseline) 
5.  Change in PGA scores (EOS and each month vs baseline) 
6. Change in BILAG numerical scores (Addition of organ scores where each A=12, B=8, C=1 and D or 
E=0).  
7. Musculoskeletal BILAG response (% with one grade drop and % who reach C or lower) 
8. Responder Analysis using the primary endpoint and assessing baseline evidence of (and changes 
in) a panel of markers selected to identify high levels of IL6/TH17 signalling, and/or B Cell signaling 
(Erk/Blys). All methods proposed have been previously standardized and are currently available in our 
laboratory as reviewed above. These will be re-standardized for the current study.  
 
Primary Biologic Endpoint (Which is a secondary endpoint for the trial):  
 
To test the applicability of baseline imbalance in a.) relative differences in the ratio of IL6/IL23/IL17 to 
Foxp3/TGFβ (suggesting T Cell signaling imbalance) OR an elevated B cell activation profile to 
predict clinical response to abatacept either through pre-dose elevation or post-dose reversal of this 
profile. Based on considerations reviewed in the preliminary data section, the primary biomarker for T  
 
 
Cell signaling impbalances will be gene expression levels of IL6/IL23/IL17 and Foxp3/TGFβ. The 
primary biomarker for T Cell signaling-induced B Cell signaling imbalance will be ERK  
 
phosphorylation after cognate interactions between T Cells and the B cell receptor as has been 
described above.  
 
This will require 8 ml of blood for several cellular response/ stimulation experiments. Follow up 
samples will be drawn at Month 3 prior to “non-responders” starting new immune suppressant 
medications, which could confound later biologic assays. This will be repeated at Month 9 to include 
changes in placebo-treated patients after 3 months on abatacept respecified Secondary Biologic 
Analyses 
 
1. Circulating cytokines of interest (Baseline Month 3 and Month 9) The cytokines to be measured 
are more easily detected in plasma than in serum. Our Serum Analyte and Biomarker Core 
has expanded extensive effort in optimizing a 51-plex cytokine assay which is based upon the 

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BioRad200 platform. Preliminary data from this approach is presented above. This will allow 
direct testing of select hypotheses, such as abtacept effects on IL-6, IFN alpha, BLyS and 
TNFRI/II pathways, but also in providing a more exploratory analysis of additional cytokines 
and chemokines important in T and B cell activation. This method uses a two laser 
immunobead multiplex technology allowing the levels of 51 cytokines to be monitored with a 
only 5-8 ml of blood. Serum levels of BLyS and APRIL will also be tested but are unable to be 
multiplexed based upon features of those analytes.  
 
2.  Abatacept Effects Relevant to Other Known B and T Cell Abnormalities of SLE (Baseline 
Month 3 and Month 9) We hypothesize that efficacy of abatacept will be related to the 
correction of one or more additional known B or T Cell abnormalities in SLE. We propose to 
assess response of immune cell subsets to cytokine stimulation or receptor signaling, as well 
as through basic immunophenotyping, to assess the influence of abatacept on the cells of 
responders (and potentially non-responders).  
 
3.  Effects of Abatacept on B Cell/T Cell gene expression (Baseline Month 3 and Month 9) 
Prespecified Analysis to determine whether select aspects of gene expression profiling by 
either microarray analyses or RNAseq (and changes after dosing) can be fit to abatacept 
pharmacodynamics and efficacy. BLyS, interferon alpha pathway expression, ICOS signaling 
panel will be primary candidates for further analysis.  
 
4. Ig production by B cells (All Visits). These will be monitored throughout the study  
 
Other Assessments: Optional Exploratory Analyses  
 
 
1. Cytokine induction assay (Baseline, Month 3 and Month 9): Induced production of 
cytokines will be measured in the supernatants of cultured (stimulated T or B cells) 
using multiplex technology.  
 
2. Functional studies (Baseline, Month 3 and Month 9) will be performed as sample 
size allows including:a. Calcium concentration in cells stimulated with anti-CD3, 
b. Protein tyrosine phosphorylation, c. Intracellular IL-2, IL17, STAT3, d. Levels 
of kinases (Syk and CaMKIV) e. Levels of pERM and ROCK  
 
Expected results: Abatacept should affect function of both T and B cells and several 
abnormalities –outlined above and routinely studied in our labs- will be corrected. The  
 
 
correction sequence will illuminate mechanism of action of abatacept (beyond the known 
blockade of costimulation) and focus future efforts at developing pharmacodynamic markers.  
 
Exploratory Clinical Correlative Studies: We propose to test the sensitivity and specificity of 
several lupus quality of life outcome measures and a physician-friendly treat to target system 
for clinical improvement and biologic changes. The primary clinical and biologic endpoints will 
be used as the standard comparators. The patient reported outcomes included will be the SF-
36, (widely used in SLE trials) and the Lupus PRO (27-29 from original application), none of 
which have been directly compared against efficacy endpoints.  
 
Exploratory Biologic Studies: Serum, plasma, urine, RNA, DNA and buffy coats will be saved 
and stored. Correlative studies will be performed using samples stored for use by BMS 

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scientists. Appendix 3, Appendix 4 and Appendix 5 describe ancillary studies to be performed 
by Dr. Thierry Dervieux of Exagen Inc, Dr. Joseph Craft of Yale University and Drs Vasileo 
Kyttaris and George Tsokos of Harvard Medical School. Appendix 6 will update any additional 
studies to be performed at BMS, and will be submitted to the IRB as an addendum. 
 
ANCILLARY STUDY BY OMRF TEAM; 
 
This Summarizes an overlapping project Submitted as Hyperaccelerated R01 (April 15, 2013):  
Joel Guthridge PI, Judith James, Joan Merrill, Mikhail Dozmorov. The entire application is also 
included along with this protocol and the Investigator’s Brochure as part of the IRB approval package. 
 
2. SPECIFIC AIMS: Systemic lupus erythematosus (SLE) is a diverse, systemic autoimmune disease 
which causes significant morbidity and early mortality, especially in minority populations and in 
women of child-bearing age. By the time patients receive the devastating SLE diagnosis, the majority 
have ongoing aggressive inflammatory processes and oftentimes damage that cannot be reversed 
(1). Clinical trials for lupus for many potential therapies have been hampered by problematic trial 
designs including 1) endpoints clouded by confusion over events which do or do not have clinical 
consequences and 2) high placebo response rates which are driven by background use of 
corticosteroids and “standard of care” medication use in the placebo arms (2, 3).  
 
Abatacept (CTLA-Ig) has been evaluated for SLE by Bristol-Myers Squibb (BMS) in moderate sized 
Phase II clinical trials for nephritis and non-nephritis SLE patients (4, 5). These previously completed 
trials failed to meet primary or secondary endpoints, but exploratory analyses suggested that the 
problematic clinical endpoints (referred to above) and aggressive background treatments might have 
impaired the interpretation of these studies. The current clinical trial “Clarification of Abatacept Effects 
in SLE with Integrated Biologic and Clinical Approaches (ABC) funded by Bristol-Myers Squibb (BMS) 
utilizes an immune suppressant withdrawal strategy coupled to endpoints which have been shown to 
provide maximal discriminatory capacity by minimizing the “noise” of minor improvements and 
clinically insignificant disease flares. This trial uses the trial design introduced in the recently 
completed Biomarkers of Lupus Disease (BOLD) study (6). 
 
Abatacept was originally developed to finely target T cell costimulation by binding CD80/CD86 on 
antigen presenting cells (APCs), thus blocking the signals delivered to T cells through CD28 (7-9). 
However, abatacept likely has effects on both APCs and T cells. The  
 
exact biologic mechanism(s) that result in improved clinical outcomes is still unclear. By partnering 
ancillary NIAMS funding to assess the immune activating and regulatory pathways in subjects from  
 
the ABC Study, we create an ideal study which needs to be considered for the hyperaccelerated 
award mechanism. The trial design of the parent study makes these particular samples invaluable for  
 
answering not only important questions about abatacept function, but also critical questions about 
mechanisms of SLE disease flare in patients off immunomodulatory drugs. Results from these studies 
will also provide information about additional biologic endpoints that allow for more appropriate SLE 
therapeutic trial designs.  
 
This application takes advantage of the novel clinical trial design of the parent ABC study to directly 
address questions about how abatacept affects 1) naïve or memory T cell activation, 2) plasma cell 
survival, 3) regulatory T cell development and 4) regulatory B cell development and function. The 
CD28:CD80/CD86 interaction is crucial in regulating these immune processes, however 
understanding whether any or all of these mechanisms function to limit clinical disease activity and/or 

ABC Trial – Version 1/08/2016 
 
50 
 
systemic 
autoimmunity 
in 
human 
SLE 
(10), 
especially 
in 
patients 
where 
background 
immunosuppressants are not used, has not been investigated. We will address these critical issues 
through the following specific aims. 
 
Specific Aim 1: Determine if abatacept reduces the number of activated T cells in the 
peripheral blood in lupus patients. Hypothesis: Since activation of naïve T cells requires 
CD80/CD86 engagement with CD28 on the T cell, blockade of this interaction by abatacept should 
reduce activated T cells in peripheral blood in patients responding to treatment with abatacept. 
 
Specific Aim 2: Evaluate if abatacept alters plasmablast survival in patients treated with 
abatacept. Hypothesis: Interactions between plasmablasts expressing counter receptors for CD28 or 
CTLA4 are important for signaling survival of plasmablasts. Treatment with abatacept may reduce 
autoantibody producing plasmablasts in peripheral blood by blocking those signals. 
 
Specific Aim 3: Characterize regulatory T cell frequencies in lupus patients in abatacept 
treatment group compared to placebo group. Hypothesis: T regulatory cell frequencies will be 
influenced by abatacept treatment of SLE patients and will help define which of the outcomes a) 
promote Treg development/ expansion or b) block Treg development leading to increased 
autoimmunity are observed clinically. 
 
Specific Aim 4: Determine whether abatacept treatment alters the development of IL-10 
producing B regulatory cells. Hypothesis: Abatacept interruption of CD28:CD80/CD86 interactions, 
which in lupus patients might be reducing Breg development or survival. This treatment may increase 
Breg frequencies and ability to better regulate autoimmune responses. 
 
Note:  Experimental approaches are summarized in the tables below and are more fully detailed in the 
full protocol submitted to NIH which is included with this protocol, along with the abatacept 
investigator brochure in the IRB submission package.  
 
Table 1: Lyoplate Immunophenotyping PBMCs. 
Table 2: Single-cell 
proteomics: Intracellular 
cytokine  

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51 
 
 
 
Table 3: Single-cell 
proteomics: 
Phosphoflow  
Table 4:

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52 
 
 
 
Figure 9: B cell subset identification using 

ABC Trial – Version 1/08/2016 
 
53 
 
 
 
 References for OMRF Biologic Study 
 
1.Rahman A, Isenberg DA. Systemic lupus erythematosus. New England Journal of  Medicine. 
2008;358(9):929-39. 
 
2.Merrill JT. Emergence of targeted immune therapies for systemic lupus. Expert Opin Emerg Drugs. 
2005;10(1):53-65. 
 
3.Merrill JT, Erkan D, Buyon JP. Challenges in bringing the bench to bedside in drug development for 
Systemic Lupus Erythematosus . Nature Reviews Drug Discov. 2004;3(12):1036-46. 
 
4.Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D'Cruz D, Wallace DJ, Bae SC, Sigal L, 
Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P. The efficacy and safety of 
abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: 
results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-
controlled trial. Arthritis Rheum. 2010;62(10):3077-87. 
 
5.Furie R, Nicholls K, Chen T, Houssiau F, Burgos-Vargas R, Chen SL, Aranda R, Meadows-
Shropshire S, Kinaszczuk M, Merrill JT. Efficacy and Safety of Abatacept Over 12 Months in Patients 
with Lupus Nephritis: Results from a Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Phase II/II Study. Arthritis & Rheumatism. 2011;63(10):S962. 
 
6.Shridharan ST, Zohou T, Immermann F, Lehmann M, Masferrer J, Honczarenko M, James JA, 
Merrill JT. Low Placebo Responses and Clinical Components of the Biomarkers of Lupus Disease 
(BOLD) Study May Provide Useful Insights for Systemic Lupus Erythematosus Clinical Trial Design. 
Arthritis & Rheumatism. 2011;63(10):S543. 
 
7.Platt AM, Gibson VB, Patakas A, Benson RA, Nadler SG, Brewer JM, McInnes IB, Garside P. 
Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on the generation of 
T follicular helper cells. J Immunol. 2010;185(3):1558-67. 
 
8.Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I, Vratsanos G, Zhou Y, 
Moreland LW. Reduction of inflammatory biomarker response by abatacept in treatment of 
rheumatoid arthritis. J Rheumatol. 2006;33(11):2162-6. 
 
9.Davidson A, Diamond B, Wofsy D, Daikh D. Block and tackle: CTLA4Ig takes on lupus. Lupus. 
2005;14(3):197-203. 
 
10.Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete 
response support conflicting conclusions. Arthritis Rheumatism. 2012; 64 (11):3660-5. 
 
 
 
 

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54 
 
 
 
 
 
Exploratory Clinical Assessments 
 
Exploratory clinical endpoints will include: 
 
Changes in CLASI, (cutaneous lupus endpoint)  
LFA REAL (Rapid, Evaluation of Activity in Lupus)  
Patient-reported outcomes: (LUPUS PRO and SF-36 domains)  
 
These analyses will be performed according to the training on the LFA POINT website (Lupus 
Foundation of America Professional Online Instrument Training) which all investigators will be 
required to use for certification. 
 
 
7 ADVERSE EVENT REPORTING 
 
7.1 Adverse Events  
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product.  
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
 
7.11 Serious Adverse Events 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see note below 
for exceptions) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention (eg, medical,  
 

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surgical) to prevent one of the other serious outcomes listed above. Examples of such events 
include but are not limited to intensive treatment in an emergency department or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
Potential drug induced liver injury (DILI) us also considered an important medical event (see 
Section 7.6 for the definition of potential DILI).  
 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs (See Section 7.5 for reporting pregnancies). 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• 
a visit to the emergency room or other hospital department lasting less than 24 hours that does 
not result in admission (unless considered an “important medical event” or a life-threatening event) 
 
• 
elective surgery planned before signing consent 
 
• 
admissions as per protocol for a planned medical/surgical procedure 
 
• 
routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
 
• 
medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry. Appropriate documentation is required in these cases. 
 
• 
admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative). 
 
7.12 Nonserious Adverse Events:  
 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
 
7.13 Assignment of Adverse Event Intensity and Relationship to Abatacept 
 
All adverse events, including those that are serious, will be graded by the investigator as follows: Mild 
(Grade 1): awareness of event but easily tolerated, Moderate (Grade 2): discomfort enough to cause 
some interference with usual activity, Severe (Grade 3): inability to carry out usual activity, Very 
Severe (Grade 4): debilitating; significantly incapacitates subject despite symptomatic therapy. 
 
The following categories and definitions of causal relationship to investigational product as determined 
by a physician should be used: Related: There is a reasonable causal relationship to investigational 
product administration and the adverse event. Not Related: There is not a reasonable causal 
relationship to investigational product administration and the adverse event. 
 
 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
(eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal 
relationship. 
 
 

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7.2 Collection and Reporting 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more adverse events. 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment required. If 
treatment for the event was administered, it should be recorded in the medical record. The 
investigator must supply BMS and the IRB/IEC with any additional information requested, notably for 
reported deaths of subjects. 
 
7.2.1 Serious Adverse Event Collecting and Reporting  
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures.  
 
All SAEs must be collected that occur within 30 days of discontinuation of dosing. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy).  
 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
All SAEs, whether related or unrelated to abatacept, and all pregnancies must be reported to BMS (by 
the investigator or designee) within 24 hours.  
All SAEs should be reported via confirmed facsimile (fax) transmission, or scanned and reported via 
electronic mail to:  
 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: <<609-818-3804>> 
 
 
MEDWATCH SAE forms will be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 

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57 
 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to the BMS using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. 
 
7.2.2 Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
 
The collection of non-serious adverse event (NSAE) information should begin at initiation of study 
drug. NSAE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. NSAEs should be 
followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also 
required for NSAEs that cause interruption or discontinuation of study drug, or those that are present 
at the end of study treatment as appropriate. All identified NSAEs must be documented appropriately. 
 
Monitoring of Blood Draws: No more than 120 cc will be drawn at major PD visits (baseline, Month 3, 
Month 6) and no more than 60 cc will be drawn at interim visits (all others).  
 
7.3 Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
 
• 
any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy  
 
 
7.4 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
an SAE. 
 
7.5 Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 6 half lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for subject safety).  
 
 

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Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy follow-
up procedures should be considered if indicated. 
 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event and 
complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours and in 
accordance with SAE reporting procedures described in Section 7.2.1  
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance 
Form. 
 
Any pregnancy that occurs in a female partner of a male study participant will be reported to BMS. 
Information on this pregnancy will be collected on a Pregnancy Surveillance Form. 
 
7.6 Potential Drug-Induced Liver Injury (DILI):Wherever possible, timely confirmation 
of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential DILI 
event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 7.2.1 for reporting details). 
 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3. No other immediately apparent and/or possible causes of AT elevation and hyperbili-
rubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver 
disease, or the administration of other drug(s) known to be hepatotoxic. 
 
 
7.7 Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
x-rays, and any other potential safety assessments, whether or not these procedures are required by 
the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.  
 
8  Data Monitoring Committee 
 
A data monitoring committee will be formed with four members and a minimum of two rheumatologists 
who are expert lupus physicians. SAE reports will be sent to the DSMB members along with IRB/BMS 
submission. Routine AEs will be reported on a quarterly basis. A full set of laboratory reports will also 
be sent to the DSMB. Flare data will also be reported, whether or not any given flare was attributed to 
adverse event or study medication. Safety reports will be reviewed quarterly or as deemed 
appropriate, based on SAE reports. The DSMB can be unblinded at request but will not be routinely 
unblinded to data, nor will efficacy data be reported during the trial, since the small number of patients 
does not justify a specific risk/benefit assessment during the course of the trial. The DSMB will be 

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provided with the safety and flare data from the previous abatacept lupus trials to use as a 
comparison to what they are reviewing. Unexpected flare or AE reports could then trigger unblinding  
 
 
of the DSMB. The DSMB may request consultation by an infectious disease or other specialist to help 
with their assessment of the data.  
 
9. Statistical Considerations 
 
Enrollment is expected to include at least 70 screened and 60 randomized subjects subjects 
have either reached a six month endpoint and/or been defined as a permanent non-responder for off 
protocol treatment or by dropping out of the protocol.  
 
The primary endpoint is the proportion of placebo vs treatment subjects who meet the primary 
endpoint of BICLA response using Chi Square analysis at month 6 as determined by an intent 
to treat analysis  
 
Subjects who drop out prematurely for any reason or are treated with off protocol medications or cross 
over to open label for lack of response at Month 3-6 are considered non responders at month 6.  
9.1 Sample Size Determination 
 
Sample Size Based on data from the BOLD study confirming the low response rates in a placebo 
group at 6 months in a study design identical to the structure of this protocol (1/41 patients or 2.4% 
met the BICLA response at 6 months in that study) and based on the assumption that the response 
rate to abatacept using this design and these endpoints would be at least equivalent to what was 
found in the Phase II Epratuzumab or Phase III BLISS studies (roughly 40-50% response). The 
sample size was optimized at 60 patients in a 1:1 randomization scheme with alpha = 0.5 and desired 
power 0.8. 
 
9.2 Populations for Analyses 
 
The subject population   As further detailed in the inclusion and exclusion criteria will consist of 
consecutive consenting lupus patients between ages 18 and 70 who have active polyarticular arthritis 
characterized by 3 or more tender and 3 or more swollen joints at the screening visit meeting the 
BILAG 2004 criteria for >/= B disease (+/- additional evidence of disease activity in other organs).   
 
The clinical justification is based on the combination of unmet need in  treating a significant, 
potentially disabling illness, while ensuring a healthy enough population to justify the risks of studying 
a biologic treatment vs placebo. 
 
Power Analysis: Chi Sq or the  Fisher’s exact test will be used for analysis. The table below has 
been powered on the assumption that the placebo group will have a result similar to (or even a bit 
more responsive than) that found in the BOLD study (which was the test prototype for this protocol to 
determine the safety and feasibility of the statistical assumptions for the placebo study). Data from the 
BOLD study confirm that there should be a near zero (2.4%) percent response by BICLA at six 
months in the placebo group in a study with background IS withdrawal. Therefore our assumption of 
at least 5% response in the placebo group in an identical trial design is reasonable.   The second 
assumption is that the treatment group will have a response rate somewhere between those found in 
the epratuzumab (by BICLA) and BLISS phase II/III (by SRI) biologic studies e.g. a predicted 
response rate between 35 and 50%. The most important basis for this assumption, however are the 
data from patients with lupus arthritis in the Phase II abatacept study, where physicians rated 40% of 

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the patients treated with abatacept as having “no flare” after baseline. Therefore this expected range 
by BICLA seems reasonable. (please see power analysis table below which is based on powering the 
primary endpoint at a range of expected response rates in treatment and placebo groups with a 
sample size of 60 patients, alpha=0.05).  
 
Power of 60 patient study if alpha=0.05 with response rates:  
 
 
Rate 1 
Rate 2 
Rate 3 
Rate 4 
Rate 5 
Rate 6 
Rate 7 
abatacept 60% 
55% 
50% 
45% 
40% 
35% 
35% 
placebo 
20% 
15% 
10% 
10% 
5% 
 5% 
3% 
power 
0.84 
0.86 
0.89 
0.80 
0.86 
0.77 
0.84 
 
 
9.3 Endpoint Definitions:  
 
9.3.1 Primary endpoint (and how it tests the study hypothesis)  
 
The primary endpoint is to compare the response rates of abatacept treated to placebo treated 
patients which addresses the main study hypothesis by specifically testing the efficacy of abatacept in 
lupus patients with active arthritis at baseline who complete a protocol designed with withdrawal of 
confounding background medications using a robust endpoint that has shown the ability to 
discriminate between effective treatment and placebo.  
 
9.3.2 Secondary and Exploratory Endpoint Definitions (see specific descriptions of endpoints in 
6.41 and 6.42, below some further discussion of the analysis plan 
 
 
9.4 Analyses To Be Performed 
 
9.4.1 Demographics and Baseline Characteristics 
 
The demographics of the patients who are likely to participate in this study should be reflective of the 
Oklahoma Lupus Cohort which will be the source for most of our recruitment activity. The age range 
of participants in this study will be between 18 and 70, and based on our experience with 
interventional trials requiring significant disease activity, we expect the majority of subjects to be 
within the ages of 25 and 55. There is no stratification scheme to be imposed based on demographics 
and baseline characteristics, but variables of age, race, gender, steroid use, autoantibody positivity, 
complement consumption, and BILAG score at baseline will be described in order to identify any 
glaring imbalances in group assignments..  
 
9.4.2 Safety Analyses 
 
In a study this size, and based on data from earlier trials of abatacept in RA and SLE it is unlikely that 
statistically significant differences will be found in overall AEs, SAEs or AEs of special interest. Safety 
Analyses will be descriptive in nature and complete in their presentation, following the examples of the 
earlier lupus and RA safety reports. 
 
9.4.3 Efficacy Analysis  

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Primary Endpoint: The primary analysis upon which this study is powered will be a two by two 
analysis of response rates to BICLA endpoint in treatment vs placebo group.  
 
Exploratory Analysis of Primary Endpoint: To address potential confounders in a small study a 
propensity score will be applied to simplify multiple variables into one variable.  
 
Analysis of Secondary Clinical Endpoints: include the BICLA and SRI response performed at each 
month using a Chi Square approach as well as mean SLEDAI, BILAG, CLASI, PGA, DIAL and PRO 
by paired T test comparing baseline to endpoint (EOS or each month) in placebo patients and 
separately in abatacept treated patients.  
 
9.4.4 Other Analyses  
 
Analysis of the Primary Biologic Endpoint (which is a secondary endpoint of the trial): Patients 
who do or do not exhibit proposed relative differences in the ratio of IL6/IL23/IL17 to Foxp3/TGFβ at 
baseline (suggesting a classic lupus T Cell signaling imbalance that might be reversed by Abatacept) 
will be compared for proportion of responders in treatment vs placebo group. Patients identified at 
baseline with TH17 hi with >/= 50% change towards normal after treatment will be compared 
separately for response rates. These endpoints will be described in terms of confidence intervals 
based on the primary clinical endpoint.  Similar analysis will be done for patients with high vs low BlyS 
or high vs low interferon alpha inducible gene expression. 
 
 
Analysis of Secondary and Exploratory Biologic Endpoints: Mean or median change in cytokine, 
immunoglobulin and gene expression levels will be explored. Bucketing of baseline profiles might be 
used to develop propensity scores suitable for a simplified refinement of the primary biologic endpoint 
by combining variables that might either increase or decrease the likelihood of response. Given the 
complex array of data we are likely to generate, principal component analysis can be applied to 
identify directions (principal components) along which the variation of the data is maximal. 
 
It should, however be pointed out that even if statistical significance is not met, a large enough effect 
size in the primary endpoint of a small pilot study this size might still be encouraging enough to 
continue development of this drug, particularly if biologic subanalyses provide insight into the 
responder profile. 
 
 
10. Study Management 
 
10.1 Compliance with the Protocol: All protocol deviations or violations will be collected 
and reported to the IRB and DSMB. Compliance with the protocol is a high priority and we will hire a 
professional study monitor to ensure compliance and accuracy in data collection. 
 
10.1.1 Compliance with the Protocol and Protocol Revisions: The study shall be 
conducted as described in this approved protocol. All revisions to the protocol must be discussed with, 
and be prepared by, BMS. The investigator should not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB/IEC of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
 

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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to: 
 
• 
IRB/IEC for review and approval/favorable opinion 
 
• 
Bristol-Myers Squibb 
 
• 
Regulatory Authority(ies), if required by local regulations 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent 
to BMS. 
 
If an amendment substantially alters the study design or increases the potential risk to the subject: (1) 
the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must be 
used to obtain consent from new subjects prior to enrollment. 
 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
10.2 Records Retention  
 
10.2.1 Records Retention: The investigator must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or institution 
procedures, or for the period specified by BMS, whichever is longer. This includes a minimum of 
fifteen years after the end of the study as per usual practice in industry supported trials. If the 
investigator withdraws from the study (eg, relocation, retirement), the records shall be transferred to a 
mutually agreed upon designee (eg, another investigator, IRB). Notice of such transfer will be given in 
writing to BMS.  
 
10.2.2 Study Drug Records: It is the responsibility of the investigator to ensure that a current 
disposition record of investigational product (those supplied by the BMS) is maintained at each study 
site where study drug and noninvestigational product(s) is/are inventoried and dispensed. In this case 
there will be one site at the Oklahoma Medical Research Foundation. Records and logs will be kept 
by our unblended pharmacy administrator within the locked pharmacy space and must comply with 
applicable regulations and guidelines and should include: 
 
• 
amount received and placed in storage area 
• 
amount currently in storage area 
• 
label ID number or batch number  
• 
amount dispensed to and returned by each subject, including unique subject identifiers 
• 
amount transferred to another area/site for dispensing or storage 
• 
non-study disposition (eg, lost, wasted)  
• 
amount destroyed at study site, if applicable 
• 
amount returned to the BMS 
• 
retain samples for bioavailability/bioequivalence, if applicable  
• 
dates and initials of person responsible for Investigational Product (IP) dispensing/accountability, 
as per the Delegation of Authority Form. 

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10.3 Destruction of Investigational Product: If the study drugs are to be destroyed on 
site, it is the investigator’s responsibility to ensure that arrangements have been made for disposal, 
and that procedures for proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. Records of the disposal must be maintained.  

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11 GLOSSARY OF TERMS 
 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 
 

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12 LIST OF ABBREVIATIONS 
AB 
Antibody  
ACR 
American College of Rheumatology  
AE 
Adverse event 
ALT 
Alanine Transaminase  
APC 
Antigen-Presenting Cell  
ARA 
American Rheumatology Association  
AST 
Aspartate Transaminase  
BCG 
Bacillus Calmette-Guérin  
BICLA 
BILAG-based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BMS 
Bristol-Myers Squibb  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count  
CDC-ACID  
Centers for Disease Control and Prevention Advisory 
Committee on Immunization Practices  
CFR 
Code of Federal Regulations  
CI 
Confidence Interval  
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index 
CMV 
Cytomegalovirus  
CRF 
Case Report Forms  
CRP 
C-Reactive Protein  
CTLA 
Cytotoxic T-Lymphocyte Associated  
CXR 
Chest X-Ray  
DIAL 
Directed Integrated Assessment of Lupus 
DMARD 
Disease-Modifying Antirheumatic Drug  
DNA 
Deoxyribonucleic Acid  
D5W 
Dextrose (5%) in Water  
EC 
European Commission  
ESR 
Expedited Safety Report  
EULAR 
European League Against Rheumatism  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyltransferase  
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor  

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HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  
HLA 
Histocompatibility Leukocyte Antigen  
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IL 
Interleukin  
IND 
Investigational New Drug (Application) 
IRB 
Independent Review Board  
IST 
Investigator-Sponsored Trial 
IU 
International Unit  
IV 
Intravenous  
JRA 
Juvenile Rheumatoid Arthritis  
MHC 
Major Histocompatibility Complex  
MRI 
Magnetic Resonance Imaging  
NPV 
Negative Predictive Value  
NS 
Normal Saline  
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-inflammatory Drug  
OA 
Osteoarthritis  
PCR 
Polymerase Chain Reaction  
PPD 
Purified Protein Derivative  
PPV 
Positive Predictive Value  
PVC 
Polyvinylchloride  
RA 
Rheumatoid Arthritis  
RF 
Rheumatoid Factor  
SAE 
Serious Adverse Event  
Se 
Sensitivity  
SLE 
Systemic Lupus Erythematosus  
SLEDAI 
SLE Disease Activity Index 
SRI 
SLE Responder Index 
SmPC 
Summary of Product Characteristics  
Sp 
Specificity  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SWFI 
Sterile Water For Injection  

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TB 
Tuberculosis  
TNF 
Tumor Necrosis Factor  
ULN 
Upper Level of Normal  
VAS 
Visual Analog Scale  
WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential  
 

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13 References 
 
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358:929-939  
 
2. Wallace D. Current and emerging lupus treatments. Am J Manag Care 2001;7(16 
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3. Merrill JT Emergence of targeted immune therapies for SLE Expert Opinion on Emerging 
Drugs Expert Opin Emerg Drugs. 2005 10:53-65.  
 
4. Merrill, JT, Erkan D and Buyon JP Challenges in bringing the bench to bedside in drug 
development for SLE.Nature Reviews Drug Discovery. 2004 3:1036-46.  
 
5. Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D'Cruz D, Wallace DJ, Bae SC, 
Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P. The efficacy 
and safety of abatacept in patients with non-life-threatening manifestations of SLE: Results of 
A 12-month exploratory study. Arthritis Rheum. 2010 62:3077-87.  
 
6. Furie R, Nicholls K, Cheng T, Houssiau F, Burgos-Vargas R, Chen SL, Aranda R, 
Meadows-Shropshire S, Kinaszczuk M and Merrill JT Efficacy and Safety of Abatacept Over 
12 Months in Patients with Lupus Nephritis: Results From a Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Phase II/III Studyl abstract at ACR 2011 (manuscript in 
preparation) 
 
7. Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, Chatham WW, Strand V, 
Weinstein A, Chevrier MR, Zhong ZJ, Freimuth WW. Novel evidence-based systemic lupus 
erythematosus responder index. Arthritis Rheum. 2009 61:1143-1151.  
 
8. Petri M, Pike M, Kelley L, Kilgallen B and Gordon PC Systemic Lupus Erythematosus 
Responder Index Assessment of Responders in EMBLEM, a Phase IIb Study in Patients with 
Moderate to Severe Systemic Lupus Erythematosus. Abstract 1378, ACR meeting Chicago, 
Nov 2011 
 
9. Sridharan ST, Zhou T, Immermann F, Lehmann M, Masferrer J, Honczarenko M, James 
JA and Merrill JT. Low Placebo Responses and Clinical Components of the Biomarkers of 
Lupus Disease (BOLD) Study May Provide Useful Insights for Systemic Lupus 
Erythematosus Clinical Trial Design. ACR annual meeting poster 1387 November 2011 
 
10. Mok C.C. and Lau C.S. Pathogenesis of systemic lupus erthematosus J Clin Pathol. 2003 
56: 481–490.  
 
11. Harley JA and Kelly J Genetic basis of systemic lupus erythematosus: a review of the 
unique genetic contributions in African Americans. J Natl Med Assoc. 2002 August; 94(8): 
670–677. 
 
12. Mohan C, Datta SK. Lupus: key pathogenic mechanisms and contributing factors. Clin 
Immunol Immunopathol 1995; 77:209. 

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13. Mountz JD, Wu J, Cheng J, Zhou T. Autoimmune disease. A problem of defective 
apoptosis. Arthritis Rheum 1994; 37:1415. 
 
14. Kotzin BL. Systemic lupus erythematosus. Cell 1996; 85:303. 
 
15. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J 
Med. 1978;298:869-871. 
 
16. Weisman, MH, Durez P, Halequa D, Aranda R, Becker J-C, Nuamah I, Vratsanos G, 
Zhou Y and Moreland LW. Reduction of inflammatory biomarker response by abatacept in 
treatment of rheumatoid arthritis. J Rheum 2006 Nov;33(11):2162-6 
 
17.Platt AM, Gibson VB, Patakas A, Benson RA, Nadler SG, Brewer JM, McInnes IB, and 
Garside P Abatacept limits breach of self-tolerance in a murine model of arthritis via effects 
on the generation of T follicular helper cells. J Immunol. 2010 Aug 1;185:1558-67 
 
18. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC, Ranchin B, Fabien N, Cochat 
P, Pouteil-Noble C, Trolliet P, Durieu I, Tebib J, Kassai B, Ansieau S, Puisieux A, Eliaou JF, 
Bonnefoy-Berard N. 2009. Interleukin 17 acts in synergy with B cell-activating factor to 
influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat 
Immunol 10:778–785  
 
19. Mitsdoerffer M, Lee Y, Jager A, Kim HJ, Korn T, Kolls JK, Cantor H, Bettelli E, Kuchroo 
VK. 2010. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc Natl Acad 
Sci USA 107:14292–14297. 
 
20. Juang YT, Peoples C, Kafri R, Kyttaris VC, Sunahori K, Kis-Toth K, Fitzgerald L, Ergin S, 
Finnell M, and Tsokos GC. A systemic lupus erythematosus gene expression array in disease 
diagnosis and classification: a preliminary report. Lupus. 2011, 20:243-9 
 
21. 2. Ritterhouse LL, S Crowe, TB Niewold , JT Merrill, VC Roberts, AB Dedeke, BR Neas, 
LF Thompson, JM Guthridge, JA James. 2011. B lymphocyte stimulator levels in SLE. 
Arthritis Rheum. In press. 
 
22. Ritterhouse LL, SR Crowe, TB Niewold, DL Kamen, SR Macwana, VC Roberts, AB 
Dedeke, JB Harley, RH Scofield, JM Guthridge, JA James. 2011. Vitamin D deficiency is 
associated with an increased autoimmune response in healthy individuals and in patients with 
SLE. Ann Rheum Dis. 70(9):1569-74.  
 
23. Crowe SR, JT Merrill, ES Vista, AB Dedeke, DM Thompson, S Stewart, JM Guthridge, TB 
Niewold, BS Franek, GM Air, LF Thompson, JA James. 2011. Influenza vaccination 
responses in human SLE: Impact of clinical and demographic features. Arthritis Rheum. 
63(8):2396-2406.  
 
24. Heinlen LD, MT McClain, LL Ritterhouse, BF Bruner, CC Edgerton, MP Keith, JA James, 
JB Harley. 2010. 60 kD Ro and nRNP A frequently initiate human lupus autoimmunity. PloS 
One. 10;5(3):e9599 

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25. Lu R, GS Vidal, JA Kelly, AM Delgado-Vega, JT Merrill, JB Harley, ME Alarcon-Riquelme 
for the BIOLUPUS and GENLES Multicenter Collaborations, SK Nath, JA James, JM 
Guthridge. 2009. Genetic associations of LYN with SLE. Genes Immun. 10(5):397-403. 
 
26. Heinlen LD, MT McClain, JT Merrill, YW Akbarali, CC Edgerton, JB Harley, JA James. 
2007. Clinical criteria of SLE precede diagnosis and associated autoantibodies are present 
before clinical symptoms. Arthritis Rheum. 56:2344-2351. Highlighted in Nature Clinical 
Practice Rheum. 
 
27. Azuma M, Ito D, Yagita H, et al. B70 antigen is a second ligand for CTLA-4 and CD28. 
Nature (London). 1993;366:76-79.  
28. Freeman GJ, Gribben JG, Boussiotis VA, et al. Cloning of B7-2: a CTLA-4 counter 
receptor that costimulates human T cell proliferation. Science. 1993; 262:909-911.  
 
29. Peach RJ, Bajorath J, Brady W, et al. Complementarity determining region 1 (CDR) and 
CDR3-analogous regions in CTLA-‘ and CD28 determine the binding to B7-1. J Exp Med. 
1994;180:2049-2058. 
 
30. A multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety 
and clinical efficacy of intravenous infusions of abatacept (BMS-188667, 2 mg/kg) given 
monthly in combination with subcutaneous injections of etanercept (25 mg given twice 
weekly) to subjects with active rheumatoid arthritis (Study IM101101). Bristol-Myers Squibb; 
2004. Document Control No. 930007559.  
 
31.Clinical Study report for IM101063: A Study To Assess The Steady-State Trough Serum 
Concentrations, Safety, And Immunogenicity Of Abatacept (BMS-188667) Administered 
Subcutaneously In Subjects With Active Rheumatoid Arthritis Who Are Receiving Disease 
Modifying Anti-Rheumatic Drugs (DMARDs). Bristol-Myers Squibb; 2008. Document Control 
No. 930025069.  
 
32. Subcutaenous abatacept Summary of Clinical Safety. Bristol-Myers Squibb, 2010. 
Document Control No. 930043734.  
 
33. Abatacept (BMS-188667) Summary of Clinical Safety. Bristol-Myers Squibb; 2010. 
Document Control No. 930043408.  
 
34 Abatacept Summary of Clinical Safety. Bristol-Myers Squibb;2005. Document Control No. 
930013008. 
 
35 Tables to Support Company Core Data Sheet for Abatacept:Adverse Events and Related 
Adverse Events in SpecificPopulations and/or Study Periods: Studies IM101100,IM101101, 
IM101102, IM101029, IM101031. Bristol-MyersSquibb; 2006. Document Control No. 
930014928. 
 
36 41 Infection, Malignancy, Autoimmune Incidence Rate Summary(Dec-2007). Bristol-Myers 
Squibb; Jul-2008. Document Control No. 930027885. 
 

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37. Interim Post-marketing Epidemiology Assessment Report,Year 2. Bristol-Myers Squibb 
Research & Development; 2010.Document Control No. 930042071.55 
 
38. Yee CS, Farewell V, Isenberg DA, Griffiths B, Teh LS, Bruce IN, Ahmad Y, Rahman A, 
Prabu A, Akil M, McHugh N, Edwards C, D'Cruz D, Khamashta MA, Maddison P, G ordon C. 
The BILG 2004 index is sensitive to change for assessment of SLE disease activity 
Rheumatology (Oxford). 2009 48:691-5.  
 
39. Kalunian K, Merrill JT, Maciucca R, Ouyang W, McBride J.M. Townsend J. Park E. 
Efficacy and safety of rontalizumab (anti-interferon splha) in SLE subjects with restricted 
immunosuppressant use: results of a randomized, double-blind, placebo-controlled Phase 2 
study Arthritis Rheumatoism 2012:64:2622 (abstract). 

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APPENDIX 1: Hybrid SLEDAI with SSFI and PGA 
(Circle in SLEDAI Score column if descriptor is present at the time of the visit or in the    
preceding 4 weeks) (The same instrument can also be used going back only ten days) 
 
Item 
no. 
SLEDAI 
SCORE 
Descriptor 
Definition 
1 
8 
Seizure 
Recent onset, exclude metabolic, infectious or drug causes 
2 
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, disorganised, or 
catatonic behaviour. Exclude uraemia and drug causes 
3 
8 
Organic brain 
syndrome 
Altered mental function with impaired orientation, memory, or other 
intellectual function, with rapid onset and fluctuating clinical 
features, inability to sustain attention to environment, plus at least 
2 of the following: perceptual disturbance, incoherent speech, 
insomnia or daytime drowsiness, or increased or decreased 
psychomotor activity. Exclude metabolic, infectious or drug causes 
4 
8 
Visual disturbance 
Retinal changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudates or hemorrhages in the choroid, or 
optic neuritis, scleritis or episcleritis. Exclude hypertension, 
infection, or drug causes 
5 
8 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving cranial 
nerves 
6 
8 
Lupus headache 
Severe, persistent headache; may be migrainous, but must be 
non-responsive to narcotic analgesia THIS WOULD RARELY BE 
ATTRIBUTED TO SLE...ALMOST NEVER SCORED 
7 
8 
CVA 
New onset Cerebrovascular accident(s). Exclude arteriosclerosis 
8 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual infarction, 
splinter hemorrhages or biopsy or angiogram proof of vasculitis 
9 
4 
Arthritis 
> 2 joints with pain and signs of inflammation (i.e. tenderness with 
swelling or effusion) 
10 
4 
Myositis 
Proximal muscle aching/weakness, associated with elevated 
creatinine phosphokinase (CK)/aldolase, or EMG changes or a 
biopsy showing myositis 
11 
4 
Urinary casts 
Heme-granular or RBC casts 
12 
4 
Hematuria 
> 5 RBC/high power field. Exclude stone, infection or other cause 
13 
4 
Proteinuria 
> 0.5 gram/24 hours 
14 
4 
Pyuria 
> 5 WBC/high power field. Exclude infection 
15 
2 
Rash 
Inflammatory type rash 
16 
2 
Alopecia 
Abnormal, patchy or diffuse loss of hair 
17 
2 
Mucosal ulcers 
Oral or nasal ulcerations 
18 
2 
Pleurisy 
Pleuritic chest pain or pleural rub or effusion, or pleural thickening 
(does not require an objective component if medically convincing) 
19 
2 
Pericarditis 
Classic pericardial pain and/or rub, effusion or ECG or 
echocardiogram confirmation (does not require an objective 
component if medically convincing) 
20 
2 
Low complement 
Decrease in CH50, C3 or C4 below lower limit of normal for testing 
laboratory  
21 
2 
Increased DNA 
Increased DNA binding above normal range for testing laboratory 

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binding 
22 
1 
Fever 
> 38ºC. Exclude infectious cause 
23 
1 
Thrombocytopenia 
< 100 x 109 platelets/L, exclude drug causes 
24 
1 
Leukopenia 
< 3 x 109 WBC/L, exclude drug causes 
SCORE:       
 
SELENA SLEDAI FLARE INDEX (Can be used with any version of the SLEDAI) 
Note as an experimental endpoint the revised SELENA SLEDAI FLARE INDEX will also be tested 
 
Physician’s Global Assessment (PGA) 
Visual Analog Scale with anchors 
 
 
0             1             2               3               (this is a three inch or 10 cm scale) 
None    Mild    Moderate   Severe 
 
 
Mild or Moderate Flare 􀂅  
 
􀂅 Change in SELENA-SLEDAI instrument score of 3 points or more (but not to more than 12) 
􀂅 New/worse:  Discoid, photosensitive, profundus, bullous lupus, 
Nasopharyngeal ulcers  
Pleuritis  
Pericarditis  
Arthritis  
Fever (SLE)  
􀂅 Increase in prednisone, but not to >0.5 mg/kg/day  
􀂅 Added NSAID or hydroxychloroquine for SLE activity  
􀂅 ≥1.0 increase in PGA score, but not to more than 2.5  
 
Severe Flare 􀂅 
 
􀂅 Change in SELENA-SLEDAI instrument score to greater than 12 
􀂅 New/worse:  CNS-SLE 
                       cutaneous vasculitis,  
Vasculitis 
Nephritis 
Myositis 
 
 
Plt <60,000 
 
 
Hemolytic anemia: Hb <70 g/L or decrease in Hb >30 g/L 
 
Requiring: double prednisone, or prednisone increase to 
>0.5 mg/kg/day, or hospitalization 
􀂅 Increase in prednisone to >0.5 mg/kg/day 
􀂅 New cyclophosphamide, azathioprine, methotrexate for SLE activity 
􀂅 Hospitalization for SLE activity 
􀂅 Increase in Physician’s Global Assessment score to >2.5 
 

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GUIDELINES FOR USE OF HYBRID SLEDAI MODIFIED FOR ASSESSMENT 
OVER 28 DAYS: TO ASSESS DISEASE ACTIVITY  
General guidelines for filling out the HYBRID SLEDAI: 
The HYBRID SLEDAI includes the definitions of proteinuria used in the 
SLEDAI 2K and is otherwise identical to the SELENA SLEDAI.  
• 
The main principle to keep in mind is that this instrument is intended to evaluate current lupus activity 
and not chronic damage, severity is accounted for in part by the "weightedness" of the scale.  
• 
Points are given exactly as defined. 
• 
A descriptor is either scored the exact points allotted or not scored, i.e. given a zero. Descriptors are 
scored only if they are present at the time of the physician encounter or in the preceding 28 days. 
Windows acceptable in a clinical trial are acceptable in scoring the SLEDAI. However, it is never 
acceptable to fill in gaps which cover activity over 2-3 months or more. The reason for this is that 
disease activity at the visit might have changed several times in such intervals and the recording of 
distant activity becomes meaningless.  
 
Please note that in the original SLEDAI the disease activity being scored was meant to cover only a ten 
day period, the modification to 28 days is a more useful assessment for use in clinical trials, in order to 
capture disease activity between monthly visits. 
• 
The descriptor must be documented by the notes written in the physician encounter form and generally 
applies to the clinical data and not to the laboratory data. The laboratory data is strictly defined as per 
cutoffs and documentation is provided by the reports from the commercial laboratory.  
• 
Descriptors do not have to be new but can be. They can be ongoing, recurrent, or initial events. Each 
would be scored the same way. An example would be a malar rash or mucosal ulcer. In these situations 
a malar rash observed at the initial visit but which remains unchanged for the next six months, 
irrespective of any treatment, is scored 2 points each time the SLEDAI is completed. Since the nature of 
lupus is that manifestations are not usually fleeting it would be rare for descriptors to be present 10 days 
before and not at the time of the encounter. This is discussed in more detail for each descriptor but is 
especially relevant for the neurologic, pulmonary, and cutaneous manifestations.  
• 
In some descriptors the exclusions written may not be exhaustive. The intent of the SLEDAI is that the 
descriptor be attributed to SLE. If the physician does not attribute the descriptor to SLE it should not be 
scored, but full documentation must be provided. 
Written in italics is the definition for each descriptor precisely provided in the SLEDAI SCORE  
SEIZURE 
Definition: Recent onset (last 28 days). Exclude metabolic, infectious or drug cause, or seizure due to past 
irreversible CNS damage. 

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This descriptor is scored if the patient has had a witnessed seizure or convincing description (such as tongue 
biting or incontinence) within 30 days of the current encounter. The patient need not have a positive EEG, CT 
scan, PET scan, QEEG, or MRI. The CSF may be totally normal. 
A seizure is also not counted: 
1. If a metabolic cause is determined. 
2. In the presence of a proven infectious meningitis, brain abscess, or fungal foci. 
3. If there is a history of recent head trauma. 
4. In the presence of an offending drug. 
5. In the presence of severe hyperthermia or hypothermia. 
6. If the patient has stopped taking anticonvulsant medication. 
7. If the patient has a documented sub-therapeutic anticonvulsant drug level. 
PSYCHOSIS 
Definition: 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. Exclude uremia and drug causes. 
This descriptor is scored if any of the criteria above are met. 
With regard to drug causes the most problematic situation is glucocorticoids. If the treating physician attributes 
the psychosis to glucocorticoids this descriptor should not be counted. 
ORGANIC BRAIN SYNDROME  
Definition: Altered mental function with impaired orientation, memory or other intellectual function, with rapid 
onset and 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. 
a. reduced capacity to focus as exemplified by new inability to perform everyday mathematical 
computations or disorientation to person, place, time, or purpose 
 
OR 
b. inability to carry on a conversation 
 
OR 
c. reduction in short term memory 
PLUS: Documented abnormality on neuropsychiatric testing  
Neuropsychiatric testing may take the form of a "mini-mental-status exam" or a formal neuropsychiatric 
examination. The important aspect for scoring OBS is that it be reversible. Consideration should be given to the 
improvement of OBS after institution of glucocorticoids. 
This descriptor is not scored in the presence of a metabolic, infectious, or drug cause. If the problem is chronic 
this descriptor is not scored in SLEDAI but is scored on the damage index.  
VISUAL DISTURBANCE 

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Definition: Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, serous exudate or 
hemorrhages in the choroid, optic neuritis, scleritis or episcleritis. Exclude hypertension, infection or drug 
causes. 
This is scored exactly as defined with the understanding that it must be supported by objective evidence. 
CRANIAL NERVE DISORDER 
Definition: New onset of sensory or motor neuropathy involving cranial nerves. Include vertigo due to lupus. 
This is scored exactly as defined with the understanding that it must be supported by objective evidence. 
However, it should be noted that hydroxychloroquine can affect the eighth cranial nerve. 
LUPUS HEADACHE 
Definition: Severe persistent headache: may be migrainous, but must be non-responsive to narcotic analgesia. 
For this descriptor to be counted, the headache must be present for greater than 24 hours and must not be 
responsive to narcotic analgesia. Objective documentation need not be present although it is expected that such 
a complaint, given the severity, would prompt formal testing such as MRI, CT, LP, etc. Furthermore, the 
headache should be of sufficient severity to warrant the initiation of glucocorticoids or additional 
immunosuppressive agents. Scoring of this descriptor means attribution of the headache to CNS lupus. 
Most headaches, including most severe and/or migrainous headaches are not attributable to lupus and this 
descriptor should only be scored very rarely. 
CVA 
Definition: New onset of cerebrovascular accident (s). Exclude arteriosclerosis or hypertensive causes. 
This descriptor is scored if the patient has had a CVA within 28 days of the current encounter. A patient 
recovering from a CVA that was documented more than 28 days prior to the current encounter is not given 
points for this descriptor. A patient may have had a previous CVA but to be scored the current CVA must be 
new. 
This descriptor is scored in the presence or absence of anti-phospholipid antibodies, i.e., the precise 
pathophysiologic mechanism need not be known. 
The CVA is scored even in the presence of a normal CT or MRI. A TIA is also scored if the patient gives a 
convincing history. To exclude atherosclerosis the patient has to have a normal carotid and/or vertebral Doppler 
and cannot have uncontrolled hypertension. 
VASCULITIS: 
Definition: Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages, or biopsy or 
angiogram proof of vasculitis. 
To score this descriptor the above definitions must be present. For example, erythematous lesions on the hands 
or feet which may be characteristically considered "leukocytoclastic vasculitis" but do not fulfill at least one of the 
above definitions and if not biopsied, are not counted. Similarly livedo reticularis is not counted. Healed ulcers 
with residual scar are not to be counted, but be sure to count these in the damage index. A lesion consistent 
with erythema nodosum should be counted regardless of whether it is biopsied or not. Purpura in the presence 
of a normal platelet count should be counted regardless of whether it has been biopsied or not. 

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ARTHRITIS 
Definition: More than two joints with pain and signs of inflammation, i.e., tenderness, swelling, or effusion. 
Arthritis is scored if it is ongoing; it need not be new or recurrent. 
Arthritis is scored only if more than two joints manifest signs of inflammation. For example if only the right 
second and left third PIPs are involved or only both wrists, points for this descriptor are not given. 
Inflammation is strictly defined in this activity index as the presence of tenderness (the patient complains of 
pain on palpating the joint or upon going through range of motion) PLUS any one of the following: 
1. swelling  
2. effusion 
3. warmth 
4. erythema, but must exclude overlying cellulitis 
The presence of tenderness alone is not sufficient. A patient's complaints of pain in specific joints without 
objective findings is not sufficient. An exception would be arthritis of the hip in which case pain in the groin on 
range of motion accompanied by decreased range of motion in the absence of swelling, warmth, or erythema 
would be counted. 
Inflammation of the tendons, ligaments, bursae, and other periarticular structures are not scored. For example 
subacromial bursitis and trochanteric bursitis are not scored. If further evaluation reveals osteonecrosis or 
osteoarthritis, this descriptor is not counted.  
MYOSITIS 
Definition: Proximal muscle aching/weakness, associated with elevated creatine phosphokinase/aldolase or 
electromyogram changes or a biopsy showing myositis. 
The patient complains of muscle aching and/or weakness in the proximal muscles PLUS one of the following 
must be present: 
1. elevated serum creatine phosphokinase and/or aldolase 
2. abnormalities on electromyogram consistent with myositis 
3. biopsy-proven myositis 
URINARY CASTS 
Definition: Heme-granular or red blood cell casts. 
This is scored if red blood cell casts are seen, even if it is only one. Pigmented casts are counted but non-
pigmented granular casts, hyaline or waxy casts are not counted. 
HEMATURIA 
Definition: >5 red blood cells/high power field. Exclude stone, infection or other cause. 
With regard to this descriptor, every attempt should be made to see patients when they are not menstruating. If 
this is not possible the urinalysis should be deferred until the next visit. 
This descriptor is not scored if there is documented renal calculi or infection. The latter must be confirmed by a 
positive urinary culture. However it is acknowledged that associated conditions such as chlamydia or urethral 

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irritation may result in mild hematuria and the physician's best judgment is warranted. The important point is 
attribution: there must be other evidence of nephritis and other causes of hematuria must be excluded.  
In the complete absence of proteinuria, attribution of hematuria to active nephritis would be very unlikely unless 
pathology is limited to the mesangium. 
PROTEINURIA 
Definition: proteinuria of more than 0.5 g/24 hours. 
Must be attributed to active lupus nephritis. 
 
PYURIA 
Definition: >5 white blood cells/high power field. Exclude infection. 
This descriptor is not scored if there is evidence of vaginal contamination (presence of any squamous epithelial 
cells) or a documented infection. The latter must be confirmed by a positive urinary culture. However, it is 
acknowledged that associated conditions such as chlamydia, trichomonas or urethral irritation may result in mild 
pyuria and the physician's best judgment is warranted. The important point is attribution; there must be 
other evidence of nephritis, and other causes of pyuria should be excluded. In the complete absence of 
proteinuria, attribution of hematuria to active nephritis would be very unlikely unless pathology is limited to the 
interstitium. 
RASH 
Definition: Ongoing inflammatory lupus rash. 
A rash is scored if it is ongoing, new or recurrent. Even if it is identical in terms of distribution and character to 
that observed on the last visit and the intensity is improved, it is counted. Therefore, despite improvement in a 
rash, if it is still ongoing it represents disease activity. The rash must be attributable to SLE. A description of the 
rash must appear in the physical exam and should include distribution, characteristics such as macular or 
papular, and size.  
The following should not be scored: 
1. Chronic scarred discoid plaques in any location. 
2. Transient malar flush, i.e., it is not raised and is evanescent 
A common problem one may encounter is the differentiation between scoring a lesion as "rash" and/or 
"vasculitis". If a lesion meets the descriptive criteria of the latter it should not also be counted as rash, i.e., the 
score would be 8 points not 10 points. If a separate rash characteristic of SLE is present only then would "rash" 
also be scored. 
ALOPECIA: 
Definition: Ongoing abnormal, patchy or diffuse loss of hair due to active lupus. 
This should be scored if any of the following conditions are present: 
1. There is temporal thinning which is newly present for less than six months (if temporal alopecia is 
present for more than six months with no change it should not be counted)  

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2. Areas of scalp with total bald spots if present for less than six months (does not need to have 
accompanying discoid lesion or follicular plugging) 
3. The presence of "lupus frizz" i.e., short of strands of unruly hair in the frontal or temporal area 
If a patient complains of hair loss and there is nothing apparent on exam this descriptor is not scored. 
MUCOSAL ULCERS: 
Definition: Ongoing oral or nasal ulcerations due to active lupus. 
An ulcer is scored if it is ongoing, it need not be new or recurrent. Ulcers can be present in either the nose or 
oral cavity. Erythema alone without frank ulceration is not sufficient to be scored, even if the erythema is present 
on the upper palate. Ulcers on the buccal mucosa and tongue are counted. 
Mucosal ulcers are not counted as vasculitis. 
PLEURISY 
Definition: Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural thickening due to 
lupus. 
This descriptor is scored if the patient complains of pleuritic chest pain lasting greater than 12 hours. The pain 
should be classic, i.e., exacerbated by inspiration, to help distinguish it from musculoskeletal conditions such as 
costochondritis, which could be confused with pleurisy. The symptom does not have to be accompanied by any 
objective findings. The presence of objective findings such as pleural rub or pleural effusions (in the absence of 
infection, congestive heart failure, malignancy, or nephrosis) is counted, even if not accompanied by symptoms. 
New pleural thickening should be counted only if other causes as described above are absent. 
PERICARDITIS: 
Definition: Classic and severe pericardial pain or rub or effusion, or electrocardiogram confirmation. 
The symptom does not have to be accompanied by objective findings.  
LOW COMPLEMENT: 
Definition: Decrease in CH50, C3 or C4 below the lower limit of normal for testing laboratory.Exclude a low C4 
or CH50 in patients with known inherited deficiency of C4. 
INCREASED DNA BINDING 
Definition: >25% binding by Farr assay or above normal range for testing laboratory. 
FEVER: 
Definition: >38°C. Exclude infectious cause. 
This would be scored if one of the following conditions are present: 
1. A documented temperature elevation >100.4°F or >38°C at the time of the visit. 
2. A convincing history from the patient that she/he has been febrile within the preceding 10 days prior to 
the visit without any signs or symptoms suggestive of infection. Febrile is defined as above and not 
simply that the patient felt feverish. In this case the patient need not be febrile at the time of the visit for 
a score of 2 to be given. 

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As stated in the SLEDAI, fever secondary to infection is not to be scored although it is acknowledged that 
concomitant lupus activity and infection can occur. Fever in the presence of infection should only be scored on 
the SLEDAI if other evidence of lupus activity is present.  
THROMBOCYTOPENIA: 
Definition: <100,000 platelets/mm3. 
LEUKOPENIA: 
Definition: <3,000 white blood cells/mm3. Exclude drug causes. 
This is exactly as described, WBC <3,000/mm3. The presence of an absolute lymphopenia does not count in the 
SLEDAI. A note of caution, do not confuse this WBC with that used to satisfy the ACR criteria for SLE which is 
WBC <3,500/mm3. 
With regard to current use of possible offending drugs, the following guidelines are to be considered: 
1. The nadir after cyclophosphamide, i.e., low WBC at 10 days after receiving cyclophosphamide in a 
patient known to have a WBC ≥ 3,000 at the time of receiving cyclophosphamide should not be counted. 
2. Do not score leukopenia appearing after initiation of a new medication known to be associated with 
leukopenia, such as azathioprine or sulfa drugs. If the patient develops a WBC <3000 while taking drugs 
which may cause leukopenia, score this only if the dosage of medication is unchanged since the last 
WBC determination. 
 
 
 
Revised SELENA SLEDAI FLARE INDEX 
 
This instrument, shown on the next pages, can be scored (experimentally 
either with only the clinical components, when clinical OR treatment 
components are met, or with the rule that “treatment trumps.” This 
instrument is still under evaluation and this study will compare these 
different scoring options.  
 
 
SELENA Flare Index-Revised 
  
 
The 2009 revision of the SELENA Flare Index evaluates increases in SLE disease activity 
within eight organ systems: mucocutaneous, musculoskeletal, cardiopulmonary, 
hematological, constitutional, renal, neurological, and gastrointestinal. 
 
 
Within each organ system the Investigator assesses clinical manifestations and treatment 
recommendations to arrive at a flare categorization as no flare, mild flare, moderate flare, or 
severe flare. 

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In the event that the assessment of a clinical manifestation and the recommendation for a 
treatment change are discrepant the treatment choice takes precedence (in the direction of 
a higher flare definition). Treatment changes recommended because of intolerance, toxicity 
or safety do not count towards a flare definition. 
  
SLE manifestations within each organ system are given on the following pages. 
 
 

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1. MUCOCUTANEOUS SYSTEM 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
New/worse/recurrent malar rash 
New/worse mild oral/nasal 
ulcers 
New/worse discoid in a small 
existing lesion or a very 
localized area such as ear 
New mild photosensitive or 
maculopapular rash 
New mild alopecia 
New mild bullous lupus 
AND/OR 
Treatment: any of 
No treatment or analgesic 
Topical treatment 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
Clinical: 
New/worse extensive oral/nasal 
ulcers 
New/worse discoid beyond a 
very localized area, such as new 
areas, enlargement, or 
deepening lesions 
New/worse moderate 
photosensitive or maculopapular 
rash 
New/worse marked alopecia 
New/worse small cutaneous 
ulcers, very limited periungual 
infarcts 
New/worse mild to moderate 
angioedema 
New/worse moderate bullous 
lupus 
New/worse mild to moderate 
panniculitis 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Two antimalarials 
Thalidomide 
Dapsone 
New/increased retinoids 
Clinical: 
New/worse extensive and/or 
severe vasculitis, 
panniculitis, 
bullous lesions, 
large cutaneous ulcers, 
desquamating, necrosis, 
gangrene, angioedema 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization 

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2. Musculoskeletal System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
New/worse/recurrent 
polyarthralgias 
New/mild arthritis of 1 or 2 joints 
AND/OR 
Treatment: any of 
No treatment or analgesia 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
New or increased NSAID 
New/increased 
dehydroepiandrosterone (DHEA) 
Clinical: 
New/worse/recurrent 
polyarthritis (3 or more joints) 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
Methotrexate < 15 mg/wk 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Intraarticular corticosteroid 
Clinical: 
New/worse/ polyarthritis (3 or 
more joints) with marked 
reduction in range of motion or 
mobility 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Methotrexate > 15 mg/wk 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 

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3. Cardiopulmonary System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
New/worse mild pleurisy or 
pericarditis (symptoms sufficient) 
AND/OR 
Treatment: any of 
No treatment or analgesic 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
New or increased NSAID 
Clinical: 
New/worse moderate pleurisy, 
pericarditis, 
small pleural effusion (with 
physical examination findings, 
radiographs or echo) 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
IV methylprednisolone if one 
dose 
Clinical: 
New/worse 
pleural or pericardial effusion 
requiring tap or window, 
tamponade 
New/worse 
pulmonary hemorrhage, 
shrinking lung 
New/worse myocarditis, 
coronary arteritis 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 

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4. Hematological System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
Leukopenia - 
new/worse/recurrent < 3,000 
Thrombocytopenia - 
New/worse/recurrent 50 to 
100,000 
Hemolytic anemia or anemia of 
active SLE - 
HCT > 30 
AND/OR 
Treatment: any of 
No treatment or analgesic 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
Clinical: 
Leukopenia - 
< 1500 but > 1000 
Thrombocytopenia - 
30 to 50,000 
Hemolytic anemia or anemia of 
active SLE - 
HCT < 30, but > 25 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Clinical: 
Leukopenia - 
< 1000 
Thrombocytopenia - 
< 30,000 or 
thrombotic microangiopathy 
Hemolytic anemia or anemia of 
active SLE - 
HCT < 25 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 
Intravenous immunoglobulin 
Plasmapheresis 

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5. Constitutional 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
Fever 
New/worse/recurrent up to 
101°F (38.3°C) 
Lymphadenopathy 
New/worse up to a few small 
cervical/axillary nodes (< 1cm) 
Weight loss 
New weight loss < 5% 
AND/OR 
Treatment: any of 
No treatment or analgesic 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
New/increased NSAID 
Clinical: 
Fever 
New/worse > 101°F (38.3°C) but 
< 103°F (39.4°C) 
Lymphadenopathy 
New/worse lymph nodes outside 
cervical chain 
Weight loss 
5% to 10% weight loss 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular steroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Clinical: 
Fever 
New/worse > 103°F (39.4°C) 
Weight loss 
> 10% weight loss 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 

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6. Renal System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
New/worse protein/cr > 0.2 but < 
0.5 
AND/OR 
Treatment: any of 
No treatment 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
Angiotensin converting enzyme 
(ACE) inhibitor, angiotensin 
receptor blocker (ARB), 
spironolactone, low protein diet, 
low sodium diet 
Statins 
Clinical: 
New/worse urine pr/cr > 0.5 but 
< 1.0 
Increase in RBC/hpf from < 5 to 
> 15 with > 2 acanthocytes/hpf 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Clinical: 
Urine pr/cr > 1.0 if baseline < 0.3 
Urine pr/cr doubled if baseline is 
> 1 
Urine pr/cr > 5.0 
New RBC casts or mixed RBC 
casts 
Biopsy with new/worse 
aggressive lesions (necrosis, 
crescents) 
Biopsy with Class IV 
Rapidly progressive 
glomerulonephritis 
Decreased GFR in last 3 months 
If baseline Cr < 2, increase of > 
0.2 mg/dl 
If baseline Cr > 2, increase of > 
0.4 mg/dl 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Mycophenolate mofetil or 
azathioprine for severe nephritis 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 

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7. Neurological System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
Minimal/intermittent ACR 
neuropsychiatric SLE syndrome 
AND/OR 
Treatment: any of 
No treatment or analgesic 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
Clinical: 
New/worsening persistent ACR 
neuropsychiatric SLE syndrome 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Clinical: 
Acute delirium or confusional 
state (organic brain syndrome) 
Coma 
Status epilepticus 
Cranial nerve palsy (including 
optic) 
Stroke due to CNS vasculitis 
Aseptic meningitis 
Mononeuritis multiplex 
Longitudinal myelitis 
Chorea 
Cerebellar ataxia 
Myositis with weakness 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 
Plasmapheresis 
Intravenous immunoglobulin 

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8. Gastrointestinal System 
 
None 
Mild 
D 
Moderate D 
Severe D 
D 
Clinical: 
New/worse LFTs > 2x normal 
but < 4x normal 
AND/OR 
Treatment: any of 
No treatment or analgesic 
New/increased 
hydroxychloroquine or other 
antimalarial 
New/increased prednisone ≤ 7.5 
mg/day 
Clinical: 
New/worse LFT’s > 4x normal 
New/worse pancreatitis with 
increased amylase, but no IV 
therapy 
New/worse clinical peritonitis 
with no ascites 
AND/OR 
Treatment: any of 
New/increased prednisone to > 
7.5 mg/day 
but  < 0.5 mg/kg/day 
for > 3 days 
Intramuscular corticosteroid 
New or increased dose of 
immunosuppressive (not 
cyclophosphamide) 
Clinical: 
New/worse lupus peritonitis with 
ascites 
New/worse enteritis, colitis or 
protein-losing enteropathy 
New/worse intestinal pseudo- 
obstruction with hypomotility 
New/worse pancreatitis requiring 
IV therapy 
New/worse GI vasculitis 
(mesenteric or other GI organ) 
AND/OR 
Treatment: any of 
New/increased prednisone > 0.5 
mg/kg/day (including IV 
methylprednisolone) 
Cyclophosphamide 
Rituximab or other biologic 
Hospitalization for severe activity 
 
 
 

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APPENDIX 2 BILAG 2004 CASE FORM 
 
 
 
 
 
Scoring:    ND    Not Done 
  
    1      Improving 
 
    2      Same 
     
 
    3      Worse 
 
    4      New 
 
   Yes/No OR Value   (where indicated) 
 
   ❑     indicate if  not due to SLE activity 
   (default is 0 = not present) 
 
1 
CONSTITUTIONAL 
1. Pyrexia - documented > 37.5ºC 
   
    ( 
    ) 
2. Weight loss - unintentional > 5% 
 
    ( 
    ) 
3. Lymphadenopathy/splenomegaly 
 
    ( 
    ) 
4. Anorexia 
 
 
 
    ( 
    ) 
 
2 
MUCOCUTANEOUS 
5. Skin eruption - severe 
 
 
    ( 
    ) 
6. Skin eruption - mild 
 
 
    ( 
    ) 
7. Angio-oedema - severe 
 
 
    ( 
    ) 
8. Angio-oedema - mild 
 
 
    ( 
    ) 
9. Mucosal ulceration - severe 
 
    ( 
    ) 
10. Mucosal ulceration - mild  
 
    ( 
    ) 
11. Panniculitis/Bullous lupus - severe  
    ( 
    ) 
12. Panniculitis/Bullous lupus - mild 
 
    ( 
    ) 
13. Major cutaneous vasculitis/thrombosis 
    ( 
    ) 
14. Digital infarcts or nodular vasculitis 
    ( 
    ) 
15. Alopecia - severe 
 
 
    ( 
    ) 
16. Alopecia - mild  
 
 
    ( 
    ) 
17. Peri-ungual erythema/chilblains 
 
    ( 
    ) 
18. Splinter haemorrhages 
 
 
    ( 
    ) 
 
3 
NEUROPSYCHIATRIC 
19. Aseptic meningitis 
 
 
    ( 
    ) 
20. Cerebral vasculitis 
 
 
    ( 
    ) 
21. Demyelinating syndrome  
 
    ( 
    ) 
22. Myelopathy 
 
 
 
    ( 
    ) 
23. Acute confusional state 
 
 
    ( 
    ) 
24. Psychosis 
 
 
 
    ( 
    ) 
25. Acute inflammatory demyelinating  
    ( 
    ) 
       polyradiculoneuropathy 
26. Mononeuropathy (single/multiplex)  
    ( 
    ) 
27. Cranial neuropathy 
 
 
    ( 
    ) 
28. Plexopathy 
 
 
 
    ( 
    ) 
29. Polyneuropathy  
 
 
    ( 
    ) 
30. Seizure disorder 
 
 
    ( 
    ) 
31. Status epilepticus 
 
 
    ( 
    ) 
32. Cerebrovascular disease (not due to vasculitis)    ( 
    )  
33. Cognitive dysfunction 
 
 
    ( 
    ) 
Only record items due to SLE Disease Activity & 
assessment refers to manifestations occurring in the last 4 
weeks (compared with the previous 4 weeks).

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34. Movement disorder 
 
 
    ( 
    ) 
35. Autonomic disorder 
 
 
    ( 
    ) 
36. Cerebellar ataxia (isolated) 
 
    ( 
    ) 
37. Lupus headache - severe unremitting  
    ( 
    ) 
38. Headache from IC hypertension 
 
    ( 
    ) 
 
4 
MUSCULOSKELETAL 
39. Myositis - severe 
 
 
    ( 
    ) 
40. Myositis - mild  
 
 
    ( 
    ) 
41. Arthritis ( severe) 
 
 
    ( 
    ) 
42. Arthritis (moderate)/Tendonitis/Tenosynovitis    ( 
    ) 
43. Arthritis (mild)/Arthralgia/Myalgia  
    ( 
    ) 
 
 
 
5 
CARDIORESPIRATORY 
44. Myocarditis - mild 
 
 
( 
) 
45. Myocarditis/Endocarditis + Cardiac failure 
( 
) 
46. Arrhythmia 
 
 
 
( 
) 
47. New valvular dysfunction  
 
( 
) 
48. Pleurisy/Pericarditis 
 
 
( 
) 
49. Cardiac tamponade 
 
 
( 
) 
50. Pleural effusion with dyspnoea 
 
( 
) 
51. Pulmonary haemorrhage/vasculitis  
( 
) 
52. Interstitial alveolitis/pneumonitis 
 
( 
) 
53. Shrinking lung syndrome  
 
( 
) 
54. Aortitis 
 
 
 
( 
) 
55. Coronary vasculitis 
 
 
( 
) 
 
6 
GASTROINTESTINAL 
56. Lupus peritonitis 
 
 
( 
) 
57. Abdominal serositis or ascites 
 
( 
) 
58. Lupus enteritis/colitis 
 
 
( 
) 
59. Malabsorption  
 
 
( 
) 
60. Protein losing enteropathy 
 
( 
) 
61. Intestinal pseudo-obstruction 
 
( 
) 
62. Lupus hepatitis  
 
 
( 
) 
63. Acute lupus cholecystitis  
 
( 
) 
64. Acute lupus pancreatitis  
 
( 
) 
 
7 
OPHTHALMIC 
65. Orbital inflammation/myositis/proptosis 
( 
) 
66. Keratitis - severe 
 
 
( 
) 
67. Keratitis - mild  
 
 
( 
) 
68. Anterior uveitis  
 
 
( 
) 
69. Posterior uveitis/retinal vasculitis - severe 
( 
) 
70. Posterior uveitis/retinal vasculitis - mild 
( 
) 
71. Episcleritis 
 
 
 
( 
) 
72. Scleritis - severe 
 
 
( 
) 
73. Scleritis - mild  
 
 
( 
) 
74. Retinal/choroidal vaso-occlusive disease 
( 
) 
75. Isolated cotton-wool spots (cytoid bodies) 
( 
) 
76. Optic neuritis  
 
 
( 
) 
77. Anterior ischaemic optic neuropathy 
( 
) 

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8 
RENAL  
78. Systolic blood pressure (mm Hg) 
  value 
( 
)  ❑ 
79. Diastolic blood pressure (mm Hg)   value 
( 
)  ❑ 
80. Accelerated hypertension                   Yes/No ( 
)   
81. Urine dipstick protein    (+=1, ++=2, +++=3) ( 
)  ❑ 
82. Urine albumin-creatinine ratio         mg/mmol ( 
)  ❑ 
83. Urine protein-creatinine ratio           mg/mmol ( 
)  ❑ 
84. 24 hour urine protein (g)  
  value 
( 
)  ❑ 
85. Nephrotic syndrome  
 
  Yes/No ( 
)   
86. Creatinine (plasma/serum) 
  mol/l ( 
)  ❑ 
87. GFR (calculated)                     ml/min/1.73 m2 ( 
)  ❑ 
88. Active urinary sediment                     Yes/No ( 
)   
89. Active nephritis  
 
  Yes/No ( 
)   
 
9 
HAEMATOLOGICAL 
90. Haemoglobin (g/dl) 
 
  value 
( 
)  ❑ 
91. Total white cell count (x 109/l) 
  value 
( 
)  ❑ 
92. Neutrophils (x 109/l) 
 
  value 
( 
)  ❑ 
93. Lymphocytes (x 109/l) 
 
  value 
( 
)  ❑ 
94. Platelets (x 109/l) 
 
  value 
( 
)  ❑ 
95. TTP  
 
 
   
( 
) 
96. Evidence of active haemolysis          Yes/No ( 
) 
97. Coombs’ test positive (isolated) 
 Yes/No ( 
) 

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BILAG-2004 INDEX GLOSSARY 
INSTRUCTIONS 
 
     • only record features that are attributable to SLE disease activity and not due to  
        damage, infection, thrombosis (in absence of inflammatory process) or other  
        conditions 
 
     • assessment refers to manifestations occurring in the last 4 weeks compared with the  
        previous 4 weeks 
 
     • activity refers to disease process which is reversible while damage refers to permanent  
        process/scarring (irreversible) 
 
     • damage due to SLE should be considered as a cause of features that are fixed/persistent  
        (SLICC/ACR damage index uses persistence  6 months to define damage) 
 
     • in some manifestations, it may be difficult to differentiate SLE from other conditions as  
        there may not be any specific test and the decision would then lies with the physician’s  
        judgement on the balance of probabilities 
 
     • ophthalmic manifestations usually need to be assessed by an ophthalmologist and these  
        items would need to be recorded after receiving the response from the ophthalmologist 
 
     • guidance for scoring: 
 
          (4) NEW  
                 • manifestations are recorded as new when it is a new episode occurring in the last   
                    4 weeks (compared to the previous 4 weeks) that has not improved and this  
                    includes new episodes (recurrence) of old manifestations  
 
                 • new episode occurring in the last 4 weeks but also satisfying the criteria for     
                    improvement (below) would be classified as improving instead of new 
 
          (3) WORSE 
                 • this refers to manifestations that have deteriorated in the last 4 weeks compared  
                    to the previous 4 weeks 
 
          (2) SAME 
                 • this refers to manifestations that have been present for the last 4 weeks and the  
                    previous 4 weeks without significant improvement or deterioration (from the  
                    previous 4 weeks) 
 
                 • this also applies to manifestations that have improved over the last 4 weeks  
                    compared to the previous 4 weeks but do not meet the criteria for improvement 
 
 
          (1) IMPROVING 
                 • definition of improvement: (a) the amount of improvement is sufficient for  
  
     
 
 
   
           consideration of reduction in therapy and  
                                                                       would not justify escalation in therapy 
 
AND   

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                                                                 (b) improvement must be present currently and 
                                                                       for at least 2 weeks out of the last 4 weeks 
 
                                                                        OR 
 
                                                                      manifestation that has completely resolved and  
                                                                      remained absent over the whole of last 1 week 
 
          (0) NOT PRESENT 
 
          (ND) NOT DONE 
                 • it is important to indicate if a test has not been performed (particularly laboratory  
                    investigations) so that this will be recorded as such in the database & not as  
                    normal or absent (which is the default) 
 
          ❑ INDICATE (TICK) IF NOT DUE TO SLE ACTIVITY 
                 • for descriptors that are based on measurements (in renal and haematology  
                    systems), it is important to indicate if these are not due to lupus disease activity  
                    (for consideration of scoring) as they are usually recorded routinely into a  
                    database 
 
          CHANGE IN SEVERITY CATEGORY 
                 • there are several items in the index which have been divided into categories of  
                    mild and severe (depending on definition). It is essential to record mild and  
                    severe items appropriately if the manifestations fulfil both criteria during the last  
                    4 weeks 
 
                 • if a mild item deteriorated to the extent that it fulfilled the definition of severe  
                    category (ie changed into severe category) within the last 4 weeks: 
       severe item scored as new (4)  
                    AND  mild item scored as worsening (3) 
 
                 • if a severe item improved (fulfilling the improvement criteria) to the extent that it  
                    no longer fulfilled the definition of severe category (ie changed into mild  
                    category) within the last 4 weeks: 
                               severe item scored as not present (0) if criteria for severe category has not  
                                                                                              been met over last 4 weeks 
                                                         or as improving (1) if criteria for severe category has been                  
                                                                                             met at some point over last 4 weeks 
 
                   AND  
 
                               mild item scored as improving (1) if it is improving over last 4 weeks 
                                                      or as the same (2) if it has remained stable over last 4 weeks 
 
 
CONSTITUTIONAL 
 
1. Pyrexia 
 
 
  
 
temperature > 37.5˚C documented 
 
2. Unintentional weight loss > 5% 
3. Lymphadenopathy 
 
 
 
lymph node more than 1 cm diameter 
 
 
 
 
 
 
 
exclude infection 
 
 

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4. Anorexia 
 
 
MUCOCUTANEOUS 
 
5. Severe eruption 
 
 
  
> 18% body surface area 
                         
any lupus rash except panniculitis, bullous lesion  
& angio-oedema 
 
body surface area (BSA) is estimated using the rules of nines 
(used to assess extent of burns) as follows: 
 
palm(excluding fingers) = 1% BSA 
         
 
 
 
each lower limb = 18% BSA 
         
 
 
 
 
 
each upper limb = 9% BSA 
         
 
 
 
 
 
 
torso (front) = 18% BSA 
        
 
 
 
 
 
  
torso (back) = 18% BSA 
         
 
 
 
 
 
 
head = 9% BSA 
         
 
 
 
 
 
 
genital (male) = 1% BSA 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. Mild eruption   
 
 
≤ 18% body surface area 
                              
 
 
 
any lupus rash except panniculitis, bullous lesion  
& angio-oedema 
 
malar rash must have been observed by a  
physician and has to be present continuously  
(persistent) for at least 1 week to be considered  
significant (to be recorded) 
 
7. Severe angio-oedema 
  
 
potentially life-threatening eg: stridor 
 
 
 
 
 
 
 
angio-oedema is a variant form of urticaria  
                                                                        which affects the subcutaneous, submucosal and  
deep dermal tissues 
 
8. Mild angio-oedema 
 
 
 
not life threatening 
 
9. Severe mucosal ulceration 
 
 
disabling (significantly interfering with oral  
                                                                        intake), extensive & deep ulceration 
 
 
 
 
 
 
 

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must have been observed by a physician 
 
10. Mild mucosal ulceration 
 
 
localised &/or non-disabling ulceration 
 
11. Severe panniculitis or bullous lupus 
 
any one: > 9% body surface area 
facial  panniculitis 
       
 
 
 
 
panniculitis that is beginning to ulcerate 
           
 
 
 
 
 panniculitis that threatens integrity of subcutaneous tissue  
(beginning to cause  surface depression) on > 9% body surface 
area, panniculitis presents as a palpable and   
tender subcutaneous induration/nodule note that established 
surface depression and atrophy alone is likely to be damage       
 
 
 
 
 
 
 
12. Mild panniculitis or bullous lupus 
≤ 9% body surface area   
does not fulfil any criteria for severe panniculitis  
 
13. Major cutaneous vasculitis/thrombosis 
resulting in extensive gangrene or ulceration or  
skin infarction 
 
14. Digital infarct or nodular vasculitis 
 
localised single or multiple infarct(s) over  
digit(s) or tender erythematous nodule(s) 
 
15. Severe alopecia 
 
 
 
clinically detectable (diffuse or patchy) hair loss  
with scalp inflammation (redness over scalp) 
 
16. Mild alopecia 
diffuse or patchy hair loss without scalp inflammation 
(clinically detectable or by history) 
 
17. Peri-ungual erythema or chilblains 
 
chilblains are localised inflammatory lesions  
                                                                         
(may ulcerate) which are precipitated by  
exposure to cold 
 
18. Splinter haemorrhages 
 
 
NEUROPSYCHIATRIC 
 
19. Aseptic meningitis 
 
 
criteria (all): acute/subacute onset 
 
 
 
 
 
 
     headache 
  
     fever 
     abnormal CSF (raised protein &/or  
          lymphocyte predominance) but negative  
          cultures 
 
preferably photophobia, neck stiffness and  
meningeal irritation should be present as well but  
are not essential for diagnosis, exclude CNS/meningeal 
infection, intracranial  haemorrhage 
 

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20. Cerebral vasculitis 
 
 
 
should be present with features of vasculitis  
in another system  
 
supportive imaging &/or biopsy findings 
 
21. Demyelinating syndrome 
 
 
discrete white matter lesion with associated   
  
 
 
 
 
 
neurological deficit not recorded elsewhere 
 
ideally there should have been at least one previously recorded 
event 
 
supportive imaging required 
 
exclude multiple sclerosis 
 
22. Myelopathy  
 
 
 
acute onset of rapidly evolving paraparesis or  
quadriparesis and/or sensory level 
 
exclude intramedullary and extramedullary  
space occupying lesion 
 
23. Acute confusional state 
 
 
acute disturbance of consciousness or level of  
arousal with reduced ability to focus, maintain or shift 
attention 
 
includes hypo- and hyperaroused states and encompasses the 
spectrum from delirium to coma 
 
24. Psychosis 
 
 
 
 
delusion or hallucinations  
 
 
 
 
 
 
 
 
 
does not occur exclusively during course of a  
delirium 
 
exclude drugs, substance abuse, primary  
psychotic disorder 
 
25. Acute inflammatory demyelinating 
 
criteria: 
       polyradiculoneuropathy 
 
 
    progressive polyradiculoneuropathy 
 
 
 
 
 
 
    loss of reflexes 
 
 
 
 
 
 
    symmetrical involvement 
 
 
 
 
 
 
    increased CSF protein without pleocytosis 
    supportive electrophysiology study 
 
26. Mononeuropathy (single/multiplex) 
 
supportive electrophysiology study required 
 
27. Cranial neuropathy 
 
 
 
except optic neuropathy which is classified  
under ophthalmic system 
 
28. Plexopathy 
 
 
 
 
disorder of brachial or lumbosacral plexus  
resulting in neurological deficit not  
corresponding to territory of single root or nerve 
 
supportive electrophysiology study required 
 
29. Polyneuropathy 
 
 
 
acute symmetrical distal sensory and/or motor  
                                                                         
deficit 

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supportive electrophysiology study required 
 
30. Seizure disorder 
independent description of seizure by reliable witness 
 
31. Status epilepticus 
 
 
 
a seizure or series of seizures lasting ≥ 30  
minutes without full recovery to baseline 
 
32. Cerebrovascular disease 
 
 
any one with supporting imaging: 
       (not due to vasculitis)  
 
    
stroke syndrome 
 
 
 
 
 
 
   transient ischaemic attack 
 
 
 
 
 
 
   intracranial haemorrhage 
 
 
 
 
 
 
 
exclude hypoglycaemia, cerebral sinus thrombosis, vascular 
malformation, tumour, abscess 
 
cerebral sinus thrombosis not included as  
definite thrombosis not considered part of lupus activity 
 
33. Cognitive dysfunction  
 
 
significant deficits in any cognitive functions: 
 
 
 
 
 
 
   simple attention (ability to register & maintain  
                                                                             
 information) 
 
 
 
 
 
 
   complex attention 
 
 
 
 
 
 
   memory (ability to register, recall & recognise  
                                                                              
information eg learning, recall) 
 
 
 
 
 
 
   visual-spatial processing (ability to analyse,  
                                                                             
 synthesise & manipulate visual-spatial  
                                                                              
information) 
 
 
 
 
 
 
   language (ability to comprehend, repeat &  
                                                                             
 produce oral/written material eg verbal  
                                                                             
 fluency, naming) 
 
 
 
 
 
 
   reasoning/problem solving (ability to reason &  
                                                                              
abstract) 
 
 
 
 
 
 
   psychomotor speed 
 
 
 
 
 
 
   executive functions (eg planning, organising,  
                                                                              
sequencing) 
 
 
 
 
 
 
 
in absence of disturbance of consciousness or  
level of arousal 
 
 
 
 
 
 
 
 
 
 
 
 
 
sufficiently severe to interfere with daily  
activities 
 
 
 
 
 
 
neuropsychological testing should be done or  
corroborating history from third party if possible  
 
 
 
 
 
 
 
exclude substance abuse 
 
34. Movement disorder 
 
 
 
exclude drugs 
 
35. Autonomic disorder 
 
 
 
any one: 
 
 
 
 
 
 
   fall in blood pressure to standing > 30/15 mm  
   Hg (systolic/diastolic) 
 
   increase in heart rate to standing ≥ 30 bpm 
 

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   loss of heart rate variation with respiration   
   (max – min < 15 bpm, expiration:inspiration  
   ratio < 1.2, Valsalva ratio < 1.4) 
 
   loss of sweating over body and limbs  
   (anhidrosis) by sweat test 
 
 
 
 
 
 
 
exclude drugs and diabetes mellitus 
 
36. Cerebellar ataxia 
cerebellar ataxia in isolation of other CNS features 
 
 
usually subacute presentation 
 
37. Severe lupus headache (unremitting) 
disabling headache unresponsive to narcotic analgesia & 
lasting ≥ 3 days 
 
exclude intracranial space occupying lesion  
and CNS infection 
 
38. Headache from IC hypertension 
 
exclude cerebral sinus thrombosis 
 
 
MUSCULOSKELETAL 
 
39. Severe myositis 
 
 
 
significantly elevated serum muscle enzymes  
  
 
 
 
 
 
with significant muscle weakness 
 
 
 
 
 
 
 
exclude endocrine causes and drug-induced  
  
 
 
 
 
 
myopathy 
 
electromyography and muscle biopsy are used for diagnostic 
purpose and are not required to determine level of activity 
 
40. Mild myositis  
 
 
 
significantly elevated serum muscle enzymes  
with myalgia but without significant muscle  
weakness 
 
 
 
 
 
 
 
asymptomatic elevated serum muscle enzymes  
not included 
 
exclude endocrine causes and drug-induced  
  
 
 
 
 
 
myopathy 
 
electromyography and muscle biopsy are used for diagnostic 
purpose and are not required to determine level of activity 
 
41. Severe arthritis 
 
 
 
observed active synovitis ≥ 2 joints with marked   
                                                                         
 loss of functional range of movements and  
                                                                                       significant impairment of activities of daily  
                                                                         
 living, that has been present on several days  
                                                                         
(cumulatively) over the last 4 weeks 
 
42. Moderate arthritis or Tendonitis 
tendonitis/tenosynovitis or active synovitis ≥ 1  

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       or Tenosynovitis  
joint (observed or through history) with some loss of 
functional range of movements, that has been present on 
several days over the last 4 weeks 
 
43. Mild arthritis or Arthralgia or Myalgia 
inflammatory type of pain (worse in the morning with 
stiffness, usually improves with activity & not brought on by 
activity) over joints/muscle  
 
inflammatory arthritis which does not fulfil the above criteria 
for moderate or severe arthritis 
 
 
CARDIORESPIRATORY 
 
44. Mild myocarditis 
 
 
 
inflammation of myocardium with raised  
cardiac enzymes &/or ECG changes and without resulting 
cardiac failure, arrhythmia or valvular dysfunction 
 
45. Cardiac failure 
cardiac failure due to myocarditis or non-infective 
inflammation of endocardium or cardiac valves (endocarditis) 
 
 
cardiac failure due to myocarditis is defined by left ventricular 
ejection fraction ≤ 40% & pulmonary oedema or peripheral 
oedema 
 
cardiac failure due to acute valvular regurgitation (from 
endocarditis) can be associated with normal left ventricular 
ejection fraction 
 
 
diastolic heart failure is not included 
 
46. Arrhythmia 
arrhythmia (except sinus tachycardia) due to myocarditis or 
non-infective inflammation of endocardium or cardiac valves 
(endocarditis) 
 
 
 
 
 
 
 
confirmation by electrocardiogram required  
(history of palpitations alone inadequate) 
 
47. New valvular dysfunction 
new cardiac valvular dysfunction due to myocarditis or non-
infective inflammation of endocardium or cardiac valves 
(endocarditis) 
 
 
 
 
 
 
 
supportive imaging required 
 
48. Pleurisy/Pericarditis 
convincing history &/or physical findings that you would 
consider treating 
 
 
in absence of cardiac tamponade or pleural effusion with 
dyspnoea 
 
                                                                        do not score if you are unsure whether or not it is pleurisy/pericarditis 
 
49. Cardiac tamponade 
 
 
supportive imaging required 
50. Pleural effusion with dyspnoea  
supportive imaging required 

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51. Pulmonary haemorrhage/vasculitis 
 
inflammation of pulmonary vasculature with  
haemoptysis &/or dyspnoea &/or pulmonary hypertension 
 
supportive imaging &/or histological diagnosis required 
 
52. Interstitial alveolitis/pneumonitis 
 
radiological features of alveolar infiltration not  
due to infection or haemorrhage required for diagnosis 
 
corrected gas transfer Kco reduced to < 70% normal or fall of 
> 20% if previously abnormal 
 
 
 
 
 
 
 
on-going activity would be determined by  
clinical findings and lung function tests, and  
repeated imaging may be required in those with  
deterioration (clinically or lung function tests) or failure to 
respond to therapy 
 
53. Shrinking lung syndrome 
 
 
acute reduction (> 20% if previous measurement  
                                                                         
available) in lung volumes (to < 70% predicted)  
                                                                         
 in the presence of normal corrected gas transfer  
                                                                         
(Kco) & dysfunctional diaphragmatic  
movements 
 
54. Aortitis 
 
 
 
 
inflammation of aorta (with or without  
dissection) with supportive imaging abnormalities  
 
accompanied by > 10 mm Hg difference in BP between arms 
&/or claudication of extremities &/or vascular bruits 
 
 
 
 
 
 
 
repeated imaging would be required to determine  
on-going activity in those with clinical  
deterioration or failure to respond to therapy 
 
55. Coronary vasculitis 
 
 
 
inflammation of coronary vessels with  
radiographic evidence of non-atheromatous narrowing, 
obstruction or aneurysmal changes 
GASTROINTESTINAL 
 
56. Lupus peritonitis 
 
 
 
serositis presenting as acute abdomen with  
rebound/guarding 
 
57. Serositis 
 
 
 
 
not presenting as acute abdomen 
 
58. Lupus enteritis or colitis 
vasculitis or inflammation of small or large bowel with 
supportive imaging &/or biopsy findings 
 
59. Malabsorption 
 
 
 
diarrhoea with abnormal D- xylose absorption  
test or increased faecal fat excretion after exclusion of 
coeliac’s disease (poor response to gluten-free diet) and gut 
vasculitis 
 
60. Protein-losing enteropathy 
 
 
diarrhoea with hypoalbuminaemia or increased  
faecal excretion of iv radiolabeled albumin after exclusion of 
gut vasculitis and malabsorption 

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61. Intestinal pseudo-obstruction 
 
 
subacute intestinal obstruction due to intestinal  
hypomotility 
 
62. Lupus hepatitis 
 
 
 
raised transaminases  
 
absence of autoantibodies specific to autoimmune hepatitis 
(eg: anti-smooth muscle, anti-liver cytosol 1) &/or biopsy 
appearance of chronic active hepatitis 
 
hepatitis typically lobular with no piecemeal necrosis 
 
exclude drug-induced and viral hepatitis 
 
63. Acute lupus cholecystitis 
 
 
after exclusion of gallstones and infection 
 
64. Acute lupus pancreatitis 
 
 
usually associated multisystem involvement 
 
 
OPHTHALMIC 
 
65. Orbital inflammation  
 
 
orbital inflammation with myositis &/or extra- 
ocular muscle swelling &/or proptosis 
 
 
 
 
 
 
 
supportive imaging required 
 
66. Severe keratitis  
 
 
 
sight threatening 
includes:  corneal melt 
peripheral ulcerative keratitis 
 
67. Mild keratitis  
 
 
 
not sight threatening 
 
68. Anterior uveitis 
69. Severe posterior uveitis &/or retinal  
 
sight-threatening &/or retinal vasculitis 
       vasculitis 
 
 
 
 
not due to vaso-occlusive disease 
 
70. Mild posterior uveitis &/or retinal 
 
not sight-threatening 
       vasculitis 
 
 
 
 
 
 
not due to vaso-occlusive disease 
 
71. Episcleritis 
 
72. Severe scleritis 
 
 
 
necrotising anterior scleritis, anterior &/or posterior scleritis  
requiring  systemic steroids/immunosuppression &/or not 
responding to NSAIDs 
 
73. Mild scleritis 
anterior &/or posterior scleritis not requiring systemic steroids 
 
 
 
 
 
 
 
 
 
 
 
 
 
excludes necrotising anterior scleritis 
 
74. Retinal/choroidal vaso-occlusive  
 
includes: retinal arterial & venous occlusion 
disease 
 
 
 
 
 
     serous retinal &/or retinal pigment  
     epithelial detachments secondary to    
     choroidal vasculopathy 
 

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75. Isolated cotton-wool spots 
 
 
also known as cytoid bodies 
 
 
 
76. Optic neuritis  
 
 
 
excludes anterior ischaemic optic neuropathy 
 
77. Anterior ischaemic optic neuropathy 
visual loss with pale swollen optic disc due to occlusion of 
posterior ciliary arteries 
 
 
RENAL 
 
78. Systolic blood pressure 
79. Diastolic blood pressure 
80. Accelerated hypertension 
 
 
blood pressure rising to > 170/110 mm Hg  
within 1 month with grade 3 or 4 Keith-Wagener-Barker 
retinal changes (flame-shaped haemorrhages or cotton-wool 
spots or papilloedema) 
 
81. Urine dipstick 
82. Urine albumin-creatinine ratio  
 
on freshly voided urine sample 
 
 
 
 
 
 
 
conversion: 1 mg/mg = 113 mg/mmol 
 
 
 
 
 
 
it is important to exclude other causes (especially  
infection) when proteinuria is present 
 
83. Urine protein-creatinine ratio 
 
 
on freshly voided urine sample 
 
 
 
 
 
 
 
conversion: 1 mg/mg = 113 mg/mmol 
 
 
 
 
 
 
 
it is important to exclude other causes (especially  
infection) when proteinuria is present 
 
84. 24 hour urine protein  
 
 
it is important to exclude other causes (especially  
infection) when proteinuria is present 
 
85. Nephrotic syndrome 
 
 
 
criteria: 
  heavy proteinuria (  3.5 g/day or protein-  
  creatinine ratio  350 mg/mmol or albumin- 
  creatinine ratio  350 mg/mmol) 
 
 
 
 
 
 
 
     hypoalbuminaemia  
 
 
 
 
 
 
     oedema 
 
86. Plasma/Serum creatinine 
 
 
exclude other causes for increase in creatinine  
(especially drugs) 
 
87. GFR  
 
 
 
 
MDRD formula: 
GFR = 170 x [serum creatinine (mg/dl)]-0.999 x   
              [age]-0.176 x [serum urea (mg/dl]-0.17 x   
              [serum albumin (g/dl)]0.318 x [0.762 if  
              female] x [1.180 if African ancestry] 
 
 
 
 
 
 
 
 
 
 
 
 
 
   units = ml/min per 1.73 m2 
 
 
 
 
 
 
   normal: male = 130 ± 40 
 
 
 
 
 
 
                 female = 120 ± 40 

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conversion: 
    serum creatinine  -  
 mg/dl = (mol/l)/88.5 
    serum urea  
        - 
 mg/dl = (mmol/l) x 2.8 
 
 
 
 
 
 
    serum albumin    -    g/dl    = (g/l)/10 
 
creatinine clearance not recommended as it is not reliable 
 
exclude other causes for decrease in GFR (especially drugs) 
 
88. Active urinary sediment 
 
 
pyuria (> 5 WCC/hpf or > 10 WCC/mm3 (l))  
 
   OR 
 
haematuria (> 5 RBC/hpf or > 10 RBC/mm3 (l)) 
 
   OR 
 
red cell casts  
 
   OR 
 
white cell casts 
 
exclude other causes (especially infection,  
vaginal bleed, calculi) 
 
89. Histology of active nephritis 
WHO Classification (1995): (any one)  
   Class III – (a) or (b) subtypes 
   Class IV – (a), (b) or (c) subtypes 
   Class V – (a), (b), (c) or (d) subtypes 
   Vasculitis 
 
 
   OR 
 
 
ISN/RPS Classification (2003): (any one) 
 
   Class III – (A) or (A/C) subtypes 
 
   Class IV – (A) or (A/C) subtypes 
 
   Class V 
 
   Vasculitis 
  
 
within last 3 months 
 
glomerular sclerosis without inflammation not included 
 
 
HAEMATOLOGICAL 
 
90. Haemoglobin  
 
 
exclude dietary deficiency & GI blood loss 
91. White cell count 
 
 
 
exclude drug-induced cause 
92. Neutrophil count 
 
 
 
exclude drug-induced cause 
93. Lymphocyte count 
94. Platelet count  
 
 
exclude thrombocytopenia of antiphospholipid  
syndrome & drug-induced cause 

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95. TTP  
 
 
 
thrombotic thrombocytopaenic purpura 
 
 
 
 
 
 
 
clinical syndrome of micro-angiopathic haemolytic anaemia 
and thrombocytopenia in absence of any other identifiable 
cause 
 
96. Evidence of active haemolysis 
positive Coomb’s test & evidence of haemolysis (raised 
bilirubin or raised reticulocyte count or reduced 
haptoglobulins) 
 
97. Isolated positive Coomb’s test 
 
 
10 
ADDITIONAL ITEMS 
 
These items are required mainly for calculation of GFR 
 
      i.  
Weight 
      ii.  African ancestry   
 
 
 
 
      iii.  Serum urea 
      iv.  Serum albumin 
 
BILAG-2004 INDEX SCORING 
 
    
• scoring based on the principle of physician’s intention to treat 
 
Category 
 
 
Definition 
 
 
A 
 
Severe disease activity requiring any of the following treatment: 
 
1. systemic high dose oral glucocorticoids (equivalent to prednisolone > 20  
    mg/day) 
 
2. intravenous pulse glucocorticoids (equivalent to pulse methylprednisolone  
    ≥ 500 mg) 
 
3. systemic immunomodulators (include biologicals, immunoglobulins and  
    plasmapheresis) 
 
4. therapeutic high dose anticoagulation in the presence of high dose steroids  
    or immunomodulators 
      eg: warfarin with target INR 3 - 4 
 
 
B 
 
 
Moderate disease activity requiring any of the following treatment: 
 
1. systemic low dose oral glucocorticoids (equivalent to prednisolone ≤ 20  
    mg/day) 
2. intramuscular or intra-articular or soft tissue glucocorticoids injection  
    (equivalent to methylprednisolone < 500mg) 

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3. topical glucocorticoids 
4. topical immunomodulators 
5. antimalarials or thalidomide or prasterone or acitretin 
6. symptomatic therapy 
      eg: NSAIDs for inflammatory arthritis 
 
 
C 
 
 
Mild disease 
 
 
D 
 
 
Inactive disease but previously affected 
 
 
E 
 
System never involved 
 
CONSTITUTIONAL 
 
Category A: 
Pyrexia recorded as 2 (same), 3 (worse) or 4 (new)  AND  
 
Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
 
 
Weight loss 
 
 
Lymphadenopathy/splenomegaly 
 
 
Anorexia 
 
Category B: 
Pyrexia recorded as 2 (same), 3 (worse) or 4 (new)  OR  
 
Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
 
 
Weight loss 
 
 
Lymphadenopathy/splenomegaly 
 
 
Anorexia 
 
BUT do not fulfil criteria for Category A 
 
Category C 
Pyrexia recorded as 1 (improving)  OR 
 
One or more of the following recorded as > 0:  
 
Weight loss 
 
 
Lymphadenopathy/Splenomegaly 
 
 
Anorexia 
 
BUT does not fulfil criteria for category A or B 
 
Category D 
Previous involvement 
 

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Category E 
No previous involvement 
 
 
MUCOCUTANEOUS 
 
Category A  
 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
 
 
Skin eruption - severe  
Angio-oedema - severe 
 
 
Mucosal ulceration - severe 
 
 
Panniculitis/Bullous lupus - severe 
Major cutaneous vasculitis/thrombosis 
 
Category B 
 
Any Category A features recorded as 1 (improving) OR  
 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
Skin eruption - mild 
Panniculitis/Bullous lupus - mild 
 
 
Digital infarcts or nodular vasculitis 
 
 
Alopecia - severe 
 
 
 
Category C  
 
Any Category B features recorded as 1 (improving) OR 
 
Any of the following recorded as > 0: 
 
 
 
Angio-oedema - mild 
 
 
Mucosal ulceration - mild 
 
 
Alopecia - mild 
Periungual erythema/chilblains 
Splinter haemorrhages 
 
Category D 
 
Previous involvement 
 
Category E 
 
No previous involvement 
 
 
NEUROPSYCHIATRIC 
CATEGORY A Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Aseptic meningitis 
Cerebral vasculitis 
Demyelinating syndrome 
Myelopathy 
Acute confusional state 
Psychosis 

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Acute inflammatory demyelinating polyradiculoneuropathy 
Mononeuropathy (single/multiplex) 
Cranial neuropathy 
Plexopathy 
Polyneuropathy 
Status epilepticus 
Cerebellar ataxia 
 
CATEGORY B Any Category A features recorded as 1 (improving) OR Any of the following 
recorded as 2 (same), 3 (worse) or 4 (new): 
Seizure disorder  
Cerebrovascular disease (not due to vasculitis) 
Cognitive dysfunction 
Movement disorder 
Autonomic disorder  
Lupus headache - severe unremitting 
Headache due to raised intracranial hypertension 
 
Category C 
Any Category B features recorded as 1 (improving) 
 
Category D  
Previous involvement 
 
Category E  
No previous involvement 
 
 
MUSCULOSKELETAL 
 
CATEGORY A Any of the following recorded  as 2 (same), 3 (worse) or 4 (new): 
 
Severe Myositis 
Severe Arthritis 
 
Category B Any Category A features recorded as 1 (improving)  OR Any of the following recorded  as 2 
(same), 3 (worse) or 4 (new): 
 
 
Mild Myositis 
Moderate Arthritis/Tendonitis/Tenosynovitis 
 
CATEGORY C Any Category B features recorded as 1 (improving) OR Any of the following 
recorded as > 0: 
 
Mild Arthritis/Arthralgia/Myalgia 
 
 
 

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CATEGORY D 
Previous involvement 
 
Category E 
 
No previous involvement 
 
 
CARDIORESPIRATORY 
 
Category A Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
Myocarditis/Endocarditis + Cardiac failure 
 
 
Arrhythmia 
 
 
New valvular dysfunction 
Cardiac tamponade 
 
 
Pleural effusion with dyspnoea 
 
 
Pulmonary haemorrhage/vasculitis  
Interstitial alveolitis/pneumonitis  
Shrinking lung syndrome 
Aortitis 
Coronary vasculitis 
 
Category B 
Any Category A features recorded as 1 (improving) OR Any of the following recorded as 2 (same), 3 (worse) or 4 
(new): 
 
Pleurisy/Pericarditis 
Myocarditis - mild 
 
Category C 
Any Category B features recorded as 1 (improving) 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
 
 
GASTROINTESTINAL 
 
CATEGORY A Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Peritonitis 
Lupus enteritis/colitis 
Intestinal pseudo-obstruction  
Acute lupus cholecystitis 
Acute lupus pancreatitis 

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CATEGORY B Any Category A feature recorded as 1 (improving) OR Any of the following 
recorded  as 2 (same), 3 (worse) or 4 (new): 
Abdominal serositis and/or ascites  
Malabsorption 
Protein losing enteropathy 
Lupus hepatitis 
 
CATEGORY C Any Category B features recorded as 1 (improving)  
 
Category D  
Previous involvement 
 
Category E   
No previous involvement 
 
 
OPHTHALMIC 
CATEGORY A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
Orbital inflammation/myositis/proptosis 
Keratitis - severe 
Posterior uveitis/retinal vasculitis - severe 
Scleritis - severe 
Retinal/choroidal vaso-occlusive disease 
Optic neuritis 
Anterior ischaemic optic neuropathy  
 
CATEGORY B 
Any Category A features recorded as 1 (improving) OR  
 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
 
 
Keratitis - mild 
Anterior uveitis 
Posterior uveitis/retinal vasculitis - mild 
Scleritis - mild 
 
CATEGORY C 
Any Category B features recorded as 1 (improving) OR  
 
Any of the following recorded as > 0: 
 
Episcleritis 
Isolated cotton-wool spots (cytoid bodies) 

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CATEGORY D 
Previous involvement 
 
CATEGORY E 
No previous involvement 
 
 
 
RENAL 
 
CATEGORY A Two or more of the following providing 1, 4 or 5 is included: 
1. Deteriorating proteinuria (severe) defined as   
(a) urine dipstick increased by ≥ 2 levels (used only if other methods of urine protein estimation not available); 
or  
      (b) 24 hour urine protein > 1 g that has not decreased (improved) by  25%; or 
      (c) urine protein-creatinine ratio > 100 mg/mmol not decreased (improved) by  25%; or 
      (d) urine albumin-creatinine ratio > 100 mg/mmol not decreased (improved) by  25% 
2. Accelerated hypertension  
3. Deteriorating renal function (severe) defined as  
      (a) plasma creatinine > 130 mol/l and having risen to > 130% of previous value; or  
      (b) GFR < 80 ml/min per 1.73 m2 and having fallen to < 67% of previous value; or  
      (c) GFR < 50 ml/min per 1.73 m2, and last time was > 50 ml/min per 1.73 m2 or not done 
4. Active urinary sediment 
5. Histological evidence of active nephritis within last 3 months  
6. Nephrotic syndrome 
 
CATEGORY B 
One of the following: 
1. One of the Category A features 
2. Proteinuria (that has not fulfilled Category A criteria) 
(a) urine dipstick which has risen by 1 level to at least 2+ (used only if other methods of urine protein 
estimation not available); or 
      (b) 24 hour urine protein ≥ 0.5 g that has not decreased (improved) by  25%; or 
      (c) urine protein-creatinine ratio ≥ 50 mg/mmol not decreased (improved) by  25%; or 
      (d) urine albumin-creatinine ratio ≥ 50 mg/mmol that has not decreased (improved) by  25% 
3. Plasma creatinine > 130 mol/l and having risen to ≥ 115% but ≤ 130% of previous value 
 
CATEGORY C 
One of the following: 
1. Mild/Stable proteinuria defined as 
(a) urine dipstick ≥ 1+ but has not fulfilled criteria for Category A & B (used only if other methods  
 of urine protein estimation not available); or 
      (b) 24 hour urine protein > 0.25 g but has not fulfilled criteria for Category A&B ; or 
      (c) urine protein-creat ratio > 25 mg/mmol but has not fulfilled criteria for Category A&B; or  

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      (d) urine albumin-creatinine ratio > 25 mg/mmol not fulfilled criteria for Category A & B 
2. Rising blood pressure (providing the recorded values are > 140/90 mm Hg) which has not fulfilled criteria for 
Category A & B, defined as  
(a) systolic rise of ≥ 30 mm Hg; and  
(b) diastolic rise of ≥ 15mm Hg  
 
CATEGORY D 
Previous involvement 
 
CATEGORY E 
No previous involvement 
 
Note: although albumin-creatinine ratio and protein-creatinine ratio are different, we use the same cut-off values for 
this index 
 
HAEMATOLOGICAL  
 
CATEGORY A 
TTP recorded as 2 (same), 3 (worse) or 4 (new)   OR Any of the following: 
 
 
Haemoglobin  
 
< 8 g/dl 
White cell count  < 1.0 x 109/l 
Neutrophil count  < 0.5 x 109/l 
 
Platelet count  
 
< 25 x 109/l 
 
CATEGORY B   
TTP recorded as 1 (improving)   OR 
 
Any of the following: 
 
Haemoglobin  
 
8 - 8.9 g/dl 
White cell count  1 - 1.9 x 109/l 
Neutrophil count  0.5 - 0.9 x 109/l 
Platelet count  
 
25 - 49 x 109/l 
Evidence of active haemolysis 
 
CATEGORY C 
Any of the following: 
Haemoglobin   
 
9 - 10.9 g/dl  
White cell count  2 - 3.9 x 109/l 
Neutrophil count  1 - 1.9 x 109/l 
Lymphocyte count  
< 1.0 x 109/L 
Platelet count 
 
50 - 149 x 109/l 
Isolated Coombs’ test positive  
CATEGORY D OR E 
Previous involvement or no Previous involvement respectively 
 

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APPENDIX 3: ANCILLARY STUDY WITH EXAGEN DIAGNOSTICS 
 
Exagen proposes to collaborate on this study under a Materials Transfer Agreement 
with OMRF which includes protocol-specific disclosures between OMRF, OMRF IRB, 
BMS and Exagen, Exagen will provide sample shipping and diagnostic testing (the FDA 
approved Lupus Avise) which includes cell bound complement testing known as 
CBCAPS at no charge. Exagen is engaged in the development and validation of 
biomarkers associated with the diagnosis and treatment optimization of patients 
affected by autoimmune diseases. The scope of this collaboration with an Investigator 
Initiated research study will include validation of the CBCAPS technology in predicting 
and/or tracking improvement after treatment as well as testing of other diagnostics in 
development at Exagen. Specific plans are below: 
CBCAPS have been offered as a diagnostic test though Exagen's clinical laboratory 
accredited by the College of American Pathologists in 2012. Anticoagulated blood (10ml 
in EDTA) will be collected and shipped overnight to Exagen Diagnostics in 
transportation kits provided. The primary objective of the research study will be to 
establish the relationship between the change in disease activity and CBCAPS levels. A 
total of 3-4 study visits are expected in the time period of the trial to include baseline, 3 
month and 6 month and/or EOS for up to 200 total CBCAPS determinations. In addition, 
the Lupus AVISE testing includes measures for antibodies to extractable nuclear 
antigens. There will be no protocol intervention into the study other than the transport of 
deidentified blood samples (which will be included in the informed consent procedures) 
and the physician will be blinded to CBCAPS results. Clinical information will also be 
withheld from Exagen until end of study.  
CBCAPS consisting of C4d deposited on erythrocytes (EC4d), B lymphocytes (BC4d), 
platelets (PC4d) and CR1 expressed on erythrocytes (ECR1 ) will be measured using a 
validated FACS assay.  
Methods: For EC4d and ECR1: whole blood (50µl) is washed with Dulbecco’s 
phosphate buffered saline, centrifuged for 5 minutes (800g) and erythrocytes pellets are 
resuspended with 500µl of 1% normal goat serum solution (Jackson Immunoresearch 
Laboratories, West Grove, PA). A 10µl erythrocyte suspension is subsequently stained 
with purified mouse monoclonal antibodies against human C4d (mouse anti human 
C4d, Quidel inc, San Diego), human CR1 (mouse anti-human antibody produced by 
Taconic Biotechnology, Hudson, NY), or alternatively using non-specific mouse anti-
human IgG1 kappa antibody (MOPC-21, BD Biosciences, San Jose, CA) for 45 minutes 
at 4°C. Samples are then washed as described above. Erythrocyte pellets are re-
suspended in a solution (25 µl) containing goat anti-mouse antibody conjugated to 
fluorescein isothiocyanate (FITC, Jackson ImmunoResearch Laboratories, West Grove, 
PA) for 45 minutes at 4°C (in the dark). Following staining, washing and resuspension 
with 250µL of cold 1% normal goat serum solution the erythrocytes are subjected to 
FACS analysis for detection of C4d or CR1 deposited on cell surface.  

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BC4d levels: following lysis of erythrocytes from whole blood (700µl) using ammonium 
chloride-based reagent (BD Pharm Lyse, BD Bioscience, San Jose, CA) and 
centrifugation (5 minutes at 800g), cell pellets are resuspended in 500µl of a 1% normal 
goat serum solution and stained using monoclonal C4d antibody (45 minutes at 2-8°C) 
as described above. A 25 µl cell suspension is subsequently stained using purified 
mouse monoclonal antibodies against human C4d or non-specific mouse anti-human 
IgG1 kappa antibody as above for 45 minutes at 4°C. Cell surface C4d staining is 
detected using goat anti-mouse fluorescein isothiocyanate (FITC) antibody (45 minutes 
at 2-8°C, dark). A monoclonal antibody against human CD-19 (CD-19 reacts with the 95 
kDa type I transmembrane glycoprotein expressed during all stages of B-cell 
differentiation and maturation) conjugated to R-phycoerythrin (R-PE) is used to detect 
the C4d complement activation derived fragment specific to the B-lymphocytes. 
PC4d levels: platelet cells obtained from patient whole blood samples are tested using 
the C4d monoclonal antibody to measure cell surface levels of C4d by FACS as above. 
Whole blood samples (50µl) are diluted and stained with the monoclonal antibody 
against human C4d  (45 minutes at 2-8ºC), followed by staining with goat anti-mouse 
conjugated to FITC (45 minutes at 2-8°C, dark). A monoclonal antibody against human 
CD-42b conjugated to R-PE is used to identify the C4d complement activation derived 
fragment specific to the platelets.  
All FACS analyses use a Beckman Coulter FC500 cytometer and CXP software 
(Beckman coulter, Brea CA). The mean fluorescence intensity (MFI) for the isotype 
background control and each complement protein (C4d, CR1) is obtained, and the net 
MFI is then determined by subtracting the non-specific MFI from the specific MFI 
results.  
A secondary objective will consist of support studies for other diagnostic test 
development to help select and guide dosage of standard of care treatments. The 
Principal Applicant for these materials at Exagen has previously applied information on 
azathioprine and methotrexate metabolism to focused pharmacologic studies and the 
current plan is to use the CBCAPS study to explore some additional questions that 
could lead to improved pharmacologic monitoring of immune suppressants that are 
currently being selected and dosed largely empirically in the lupus population. The 
proposed exploratory studies will be to study (without interfering with) the standard of 
care changes that will be applied in the protocol over serial visits) and explore the 
relationship of drug levels of immunosuppressants and their metabolites with outcomes. 
Biological materials including plasma, red cells and genetic materials from consenting 
patients will be stored for future correlation studies of pathway metabolites with relevant 
treatment-induced pharmacodynamic changes. Plasma, red cells and genetic materials 
will be extracted from the same small whole blood sample received for CBCAPS 
analysis.  For example this might include correlation of adenosine pathway-induced 
inflammatory signals vs. lymphocyte subset markers to clinical efficacy and 
pharmacokinetic markers (e.g. metabolites of 6 mercaptopurine in the case of 
azathioprine or methotrexate polyglutamates in the case of methotrexate).  The goal is 
to improve the diagnostic capabilities of tests supportive of improved pharmacologic 

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application of standard of care interventions in SLE by specific identification of relevant 
proteomic and genomic markers associated with treatment efficacy and outcome of 
SLE. In collaborative work, these findings may be integrated with the results of other 
biomarkers being studied by other teams working on the ABC study. 
For Methotrexate polyglutamate and azathioprine levels determination the method will 
used liquid chromatography (Dervieux et al Clin Chem 2003; Dervieux et al Clin Chem 
1998),  a portion of whole blood received for CBCAPS analysis will be centrifuged and 
red cells pellets will be washed with saline. Following red cell lysis packed RBC 
hemolysate will be homogenized with water and perchloric acid will be added to the 
mixture, vortexed and centrifuged. The acidic supernatant will be directly injected onto 
the HPLC system for MTXPG analysis while a portion will be heated for one hour to 
hydrolyze azathioprine nucleotides to their respective base. The HLPC separation will 
be achieved with linear gradient of acetonitrile on reversed phase colums. MTXPG 
photolytic product will be measured using flurometric detection while azathioprine 
metabolites will be measured using UV. Results will be reported as nmol/L packed red 
blood cells.  
 
Materials Transfer Agreement Exagen will be restricted to the studies described in a 
Materials Transfer Agreement between Exagen and OMRF prior to the shipment of 
samples. 
 
Study of Abatacept Levels is Not Approved For This Protocol. Exagen requested 
from BMS the possibility of studying Abatacept levels in the samples. This has not been 
approved and it is agreed that Exagen will be prohibited from doing so at this time.  

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APPENDIX 4: Ancillary Project to be Performed by Dr. Joseph Craft, 
Yale University 
 
This project will track phenotypic changes in T follicular helper cells before and after 
treatment with abatacept. These findings will be correlated with clinical results and 
might later be compared to other biomarker studies being performed by members of the 
ABC team at the discretion of Dr. Craft. A Materials Transfer Agreement will be 
developed between OMRF and Yale University to govern this project and the use of 
blood samples. A summary of this project, written by Dr. Craft is below: 
 
Significance. Systemic lupus erythematosus (SLE) is characterized by the generation 
of pathogenic autoantibodies. In both humans and mice with lupus, such autoantibodies 
undergo affinity maturation, indicative of a breakdown in germinal center (GC) B cell 
tolerance1. In GCs, T follicular helper (Tfh) cells provide B cells with survival and 
differentiation signals, including CD40 ligand (CD40L), programmed death receptor-1 
(PD-1), and IL-21, essential for B cell selection with maturation into memory B cells and 
long-lived antibody-secreting (plasma) cells, as we have recently reviewed2,3).  
Dysfunctional Tfh cells are likely to be a main contributor to the development of 
systemic autoimmunity4-6, a notion supported by the finding that abrogation of Tfh cell 
development or function in murine lupus is therapeutically beneficial, as we and others 
have shown5-9. Yet, the exact role of these cells in the genesis of immune, and in 
particular, autoimmune responses, remains incompletely understood, as does their 
post-GC fate and their contribution, if any, to the pool of memory T cells that provides B 
cell help for recall responses in mice and in humans10-13, and that are presumably 
important in recall of pathogenic autoreactive memory B cells in patients with SLE. The 
goal of our proposal is to seek and identify these cells in the blood of humans with SLE, 
during and after remittitive therapy. Our specific aim is to:  
Aim: Seek and characterize circulating follicular helper T cells in patients with 
SLE, during and after therapy that potentially alters their development and ability 
to promote autoreactive, and pathogenic, B cell activation.  
Methods 
We will analyze PBMCs from patients (1-2 green [heparinized] top tubes, shipped 
overnight), asking if they have circulating Tfh (cTfh) cells, and assessing their 
phenotype and their relationship to disease activity and therapeutic intervention. We 
plan to enumerate cTfh and CD4 T central memory (Tcm) cells, respectively; as Tcm 
cells home to follicles of SLOs, and perhaps contribute to reactivation of atuoreactive 
memory B cells therein, the residence of Tfh cells, it is critical to distinguish these 
populations.  Markers to be used for cTfh cells include CXCR5, ICOS, IL-21, and PD-1, 
with CCR7 and CD62L added to distinguish Tcm cells.  We will also determine the 
frequency of plasmablasts, correlating them with disease activity. We anticipate that 
CXCR5hiICOShiPD-1hi CD4 T (cTfh) cells will be expanded in SLE patients, with 
decreases following appropriate therapeutic intervention, and corresponding increases 
upon tapering of therapeutic agents. cTfh cells should be IL-21 competent with lower 
expression of CCR7, the latter compared to Tcm cells, enabling the distinction between 
these subsets. PD-1, but not ICOS or CXCR5, expression should be elevated in cTfh 

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cells from SLE patients compared to controls, with its MFI correlated with the SLE 
activity (SLEDAI), circulating plasmablasts, and anti-dsDNA antibody titers.  
We anticipate that these results will demonstrate that cTfh cells will be associated with 
disease activity in SLE, and suggest their presence indicates aberrant homeostasis of 
T-B cell collaboration and a causal relationship central to disease pathogenesis. We 
also expect to underscore the idea that Tfh cells are a valid therapeutic target in SLE.  
References 
1. Vinuesa, C. G., Sanz, I. & Cook, M. C. Dysregulation of germinal centres in 
autoimmune disease. Nat Rev Immunol 9, 845-857 (2009). 
2. Craft, J. E. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev 
Rheumatol, doi:10.1038/nrrheum.2012.58 
nrrheum.2012.58 [pii] (2012). 
3. Weinstein, J. S., Hernandez, S. G. & Craft, J. T cells that promote B-Cell maturation 
in 
systemic 
autoimmunity. 
Immunol 
Rev 
247, 
160-171, 
doi:10.1111/j.1600-
065X.2012.01122.x (2012). 
4. Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress 
follicular helper T cells and autoimmunity. Nature 435, 452-458 (2005). 
5. Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG 
production via IL-21 in systemic autoimmunity. J Exp Med 205, 2873-2886, 
doi:jem.20080840 [pii] 
10.1084/jem.20080840 (2008). 
6. Bubier, J. A. et al. A critical role for IL-21 receptor signaling in the pathogenesis of 
systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A 106, 1518-
1523, doi:0807309106 [pii] 
10.1073/pnas.0807309106 (2009). 
7. Iwai, H. et al. Involvement of inducible costimulator-B7 homologous protein 
costimulatory pathway in murine lupus nephritis. J Immunol 171, 2848-2854 (2003). 
8. Herber, D. et al. IL-21 has a pathogenic role in a lupus-prone mouse model and its 
blockade with IL-21R.Fc reduces disease progression. J Immunol 178, 3822-3830 
(2007). 
9. Vugmeyster, Y. et al. In vitro potency, pharmacokinetic profiles, and pharmacological 
activity of optimized anti-IL-21R antibodies in a mouse model of lupus. MAbs 2, 335-
346, doi:11850 [pii] (2010). 
10. Morita, R. et al. Human Blood CXCR5+CD4+ T Cells Are Counterparts of T 
Follicular Cells and Contain Specific Subsets that Differentially Support Antibody 
Secretion. Immunity (2011). 
11. Bentebibel, S.-E., Schmitt, N., Banchereau, J. & Ueno, H. Human tonsil B-cell 
lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside 
germinal 
centers. 
Proceedings 
of 
the 
National 
Academy 
of 
Sciences, 
doi:10.1073/pnas.1100898108 (2011). 
12. MacLeod, M. K. et al. Memory CD4 T cells that express CXCR5 provide accelerated 
help to B cells. J Immunol 186, 2889-2896, doi:jimmunol.1002955 [pii] 
10.4049/jimmunol.1002955 (2011). 
13. Pepper, M., Pag·n, A. J., Igy·rtÛ, B. Z., Taylor, J. J. & Jenkins, M. K. Opposing 
Signals from the Bcl6 Transcription Factor and the Interleukin-2 Receptor Generate T 
Helper 1 Central and Effector Memory Cells. Immunity 35, 583-595 (2011). 

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APPENDIX 5 ANCILLARY STUDY TO BE PERFORMED BY DR VASILEO 
KYTTARIS AND DR GEORGE TSOKOS OF HARVARD UNIVERSITY  
 
Rationale: T cells from patients with systemic lupus (SLE) have a strong calcium 
response (1) to T Cell Receptor engagement. This causes egress of the transcription 
factor NF-ATc2 into the nucleus at higher rates than is found in healthy volunteers (2,3). 
The enhanced T Cell response may be due to aggregation of lipid rafts (4), substitution 
of CD3-chain/ZAP-70 signaling by Fc receptor (FcR)/Syk (5,6), and/or mitochondrial 
hyperpolarization (7) SLE T cells have been found to provide aberrant help to B cells 
leading to increased expression of costimulatory molecules, such as CD154, (or 
CD40L) (8) with infiltration into diseased tissue by specialized T cells which produce the 
proinflammatory cytokine interleukin-17 (IL-17) (9). In a recent study, we demonstrated 
that MRL/lpr mouse T cells provide aberrant help to normal mouse B cells in a 
calcineurin dependent manner, linking SLE T cell hyperactivity to T cell helper function. 
Moreover, we showed that the enhanced calcium/calcineurin/NF-AT pathway in human 
and murine SLE T cells can be suppressed in the presence of dipyridamole, a recently 
recognized specific inhibitor of calcineurin–NF-AT interactions (10). Finally, 
administration of dipyridamole to MRL/lpr mice improved disease pathology. 
 
Since abatacept interferes with cognate B and T cell interactions and may influence the 
phenotype and/or prevalence of IL-17 producing T cells, we propose to study SLE 
samples before, during and after treatment with abatacept or placebo in order to 
determine the impact of this treatment on T Cell stimulated cytokine production. 
 
Methods: Isolation and Stimulation of T Cells for Assessment: T cells will be 
isolated from peripheral blood samples (20 cc) at OMRF by negative selection using a 
magnetic bead process that is in frequent use at OMRF. Cells will be incubated in RPMI 
1640 medium with 10% (volume/volume) heatinactivated fetal calf serum (FCS; Sigma-
Aldrich) supplemented with L-glutamine and 100 units of penicillin and 100 _g of 
streptomycin per ml. These incubations will take place in a culture incubator at a 
temperature of 37°C in a humidified atmosphere containing 5% CO2.  Cells will be 
stimulated with plate-bound anti-CD3 antibody and anti-CD28 antibody for 48 hours. To 
achieve this 24 well plates will be coated with anti-CD3 and anti-CD28 antibodies in 1 
mL of PBS in each well and the well plate incubated for 2 hr in 37C prior to emptying the 
wells and adding the cell suspension. Supernatant will be isolated from 0, 24, 48 hour 
cultures and frozen until batched shipments to Boston are possible. The cells will then 
be lysed in RLT buffer for retrieval of mRNA.   
 
After transfer of these pre-processed samples to Boston, immunoglobulin and 
cytokines will be measured by enzyme-linked immunosorbent assay (ELISA) 
according to the manufacturer’s instructions using a kit from Immunology Laboratories. 
Human CD154 and murine CD154 were measured using an ELISA kit from R&D 
Systems and an ELISA kit from PromoCell, respectively, according to the 
manufacturers’ instructions. Human cytokines will be measured using flow cytometry–
based cytokine bead array systems (BD Biosciences). 
 

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REFERENCES 
 
1. Vassilopoulos D, Kovacs B, Tsokos GC. TCR/CD3 complex mediated signal 
transduction pathway in T cells and T cell lines from patients with systemic lupus 
erythematosus. J Immunol 1995;155:2269–81. 
2. Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. Increased levels of NF-
ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic 
lupus erythematosus. J Immunol 2007;178:1960–6.  
3. Mehta J, Genin A, Brunner M, Scalzi LV, Mishra N, Beukelman T, et al. Prolonged 
expression of CD154 on CD4 T cells from pediatric lupus patients correlates with 
increased CD154 transcription, increased nuclear factor of activated T cell activity, and 
glomerulonephritis. Arthritis Rheum 2010;62:2499–509. 
4. Krishnan S, Nambiar MP, Warke VG, Fisher CU, Mitchell J, Delaney N, et al. 
Alterations in lipid raft composition and dynamics contribute to abnormal T cell 
responses in systemic lupus erythematosus. J Immunol 2004;172:7821–31. 
5. Krishnan S, Juang YT, Chowdhury B, Magilavy A, Fisher CU, Nguyen H, et al. 
Differential expression and molecular associations of Syk in systemic lupus 
erythematosus T cells. J Immun 2008;181:8145–52. 
6. Krishnan S, Warke VG, Nambiar MP, Tsokos GC, Farber DL. The FcR_ subunit and 
Syk kinase replace the CD3 _-chain and ZAP-70 kinase in the TCR signaling complex 
of human effector CD4 T cells. J Immunol 2003;170:4189–95. 
7. Nagy G, Barcza M, Gonchoroff N, Phillips PE, Perl A. Nitric oxide-dependent 
mitochondrial angiogenesis generates Ca2_ signaling profile of lupus T cells. J Immunol 
2004;173:3676–83. 
8. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 
ligand by B and T cells in human lupus and its role in pathogenic autoantibody 
production. J Clin Invest 1996;97:2063–73. 
9. Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. 
Expanded double negative T cells in patients with systemic lupus erythematosus 
produce IL-17 and infiltrate the kidneys. J Immunol 2008;181:8761–6. 
10. Vasileios C. Kyttaris, Zheng Zhang, Ourania Kampagianni, and George C. Tsokos 
Calcium Signaling  in Systemic Lupus Erythematosus T Cells Arthritis Rheum 
2011:63:2058–2066 
 
 

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APPENDIX 6: STUDIES BY BMS TRANSLATIONAL R&D, PK TEAM, GENETICS 
and EPIGENETICS TEAMS 
 
Rationale:     
 
1. Patient Subset and PD Analyses: To expand on the proposed biomarker endpoints 
incorporated into the study, and further support the goal of identifying phenotypes and 
or signatures that may stratify patients with regard to clinical response to abatacept, 
BMS proposes to interrogate additional mechanism based and exploratory biomarkers 
as well as perform additional data analyses using clinical samples from this study. 
 
2. PK and immunogenicity studies: To better understand dose/effects and to illuminate 
PD analysis. 
 
EXPERIMENTAL PLAN 
 
Correlation of target and pathway-specific receptor levels with clinical response. 
Aberrant receptor expression and numerous dysregulated signaling pathways in 
peripheral T/B lymphocytes and other antigen presenting cells (APCs; monocytes, 
dendritic cells), leading to auto-antibody production, are associated with SLE disease 
pathogenesis, and support the development of co-stimulation blockade inhibitors, i.e. 
abatacept, for therapeutic intervention2,3. This proposed analysis would measure 
baseline levels of constitutively expressed receptors in the co-stimulation cascade, 
including CD28, CD40 and CD86 on T cell subsets, B cell subsets, monocytes and 
dendritic cells using flow cytometric methods, for correlation with clinical response 
measures. .A similar analysis was performed measuring CD28 levels in rheumatoid 
arthritis patients treated with abatacept. In this study, decreases in CD4+ and CD8+ / 
CD28 negative T cells were observed over 48 weeks of abatacept treatment, and 
correlated with improvements in the DAS28-CRP score 1. For the ABC study, baseline 
receptor levels will be tracked in a similar manner and evaluated for changes from 
baseline as well as correlations with changes in disease indices. 
 
Evaluation of soluble and cell surface activation markers for correlation with 
clinical 
response. 
Inducible 
co-stimulatory 
molecules 
are 
often 
expressed 
constitutively on peripheral leukocytes in SLE patients, indicating a chronically activated 
phenotype2,3,4. Moreover, soluble receptors associated with B7/TNFR family members 
have been observed at elevated levels in SLE patients and are associated with 
increased disease severity. 5 Using flow cytometric and multiplex serum methods, we 
will measure a panel of co-stimulation-related molecules on peripheral leukocytes as 
well as in serum samples that may both correlate with clinical response and show 
pharmacodynamic changes over the course of abatacept treatment. These will include, 
but are not limited to cell surface CD25, CD69 and CD40L, ICOS, PD-1, CD244, CD80, 
HLA-DR and others on leukocyte immunophenotypes. Pro-inflammatory serum analytes 
will include but are not limited to sCD30, sIL-1RI and II, sIL-2Rα, sIL-4R, sIL-6R, 

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sTNFRI and II, FLT3L6, solCD62L, pentraxin 3, APRIL, TWEAK, ST-2, and a-defensin 
3. Exploratory analyses of urine analytes will also be performed and will include but are 
not limited to uMCP-1, uTWEAK, uNGAL,and IL-18.  
 
Evaluation of gene expression profiled related to  T cell / APC mRNA pathway 
signatures, Unpublished studies from BMS laboratories have identified genes that are 
up- or down-regulated during activation of specific co-stimulatory pathways, e.g., anti-
CD3/CD28 stimulation of T cells, and soluble CD40L stimulation of B cells and dendritic 
cells. It is therefore of interest to interrogate mRNA profiles from patients for mRNA 
signatures indicating an activated T cell / APC phenotype, for correlation with clinical 
response. Additionally, we propose to track changes in these pathway-specific profiles 
to evaluate the impact of abatacept treatment on mRNA levels. 
 
Measurement of complement C3d deposition on T cells as a measure of T cell 
responsiveness. A recent publication identified complement C3d deposition on T cells 
at increased levels in SLE patients versus healthy controls. C3d deposition was 
associated with decreased calcium responsiveness and increased cytokine production, 
and appeared to localize at lipid rafts7. Given that T cell:APC co-stimulation also co-
localizes to lipid raft regions, it will be informative to ascertain the effects, if any, of 
abatacept treatment on C3d+ T cell levels over time for correlation with cytokine 
responsiveness. C3d+ T cells may represent a hyperactive subpopulation that 
contributes to the pathogenesis of SLE. 
 
Methods and analysis. CD4+ and CD8+ T cell subtypes, including naive, central and 
effector memory T cells, double negative (DN), Tfh8, and CD3+ γδ T cells, naive and 
memory Bs cells, plasmablasts, monocytes, plasmacytoid and myeloid dendritic cells for 
cell surface or intracellular expression of pathway-related markers. Frequency of the 
above cell subtypes will also be tracked as a percentage of total T cells, B cells, or 
leukocytes. Samples will be analyzed by multicolor flow cytometry using established 
phenotypic markers. Soluble receptor panels in serum or plasma will be analyzed by 
Luminex, other multiplex technologies, or ELISA.  
 
While this study is not statistically powered for detailed SNP analysis, samples will be 
assessed to determine the frequency of both disease-associated (e.g. PDCD1, RUNX1, 
PTPN2, IRF5) and pathway-associated (e.g. CTLA4, CD28, ICOS) SNPs that have 
demonstrated associations with SLE disease susceptibility. Additionally, gene-specific 
DNA methylation changes have been demonstrated to occur in SLE and also may have 
associations with SLE disease severity and flare. DNA samples will collected for whole 
genome DNA methylation analysis. More extensive mRNA profiling may be performed 
using Affymetrix for whole genome profiling, or targeted mRNA panels may be analyzed 
by TLDA,OpenArray or other technologies. 
 
PBMCs will be isolated, frozen and banked, then batch analyzed for C3d levels on 
resting T cells, cytokine levels (e.g., IL-2, IL-4, γIFN and IL-17) and C3d levels following 
anti-CD3/anti-CD28 stimulation. In addition to C3d deposition, other functional studies 
may be performed, including but not limited to mitogen and antigen response assays. 

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Additional Genomic DNA analysis and epigenetic evaluation. While this study is not 
statistically powered for detailed SNP analysis, we propose to collect samples to 
determine the frequency of both disease associated (e.g. PDCD1, RUNX1, PTPN2, 
IRF5) and pathway-associated (e.g. CTLA4, CD28, ICOS) SNPS that have 
demonstrated associations with SLE disease susceptibility. 
 
Additionally, gene-specific DNA methylation changes have been demonstrated to occur 
in SLE and also may have associations with SLE disease severity and flare. DNA 
samples will be collected for whole genome DNA methylation analysis.  
 
PK Studies:   
 
1. PK samples at baseline (Day 1) and at pre-dose of Months 1 (Day 28), 2 (Day 57), 3 
(Day 85), 4 (Day 113), and with matching immunogenicity at month 6 (Day 169) in the 
DB period, as well as at follow-up visits at Months 7, 8 and 12 will be analyzed for 
Abatacept treated patients. These data can provide information of immunogenicity rate 
and trough drug levels following 125 mg SC Orencia in SLE.  The results are also useful 
for comparison with IV Orenca as well as to gain some understanding of how to 
interpret PD variables.  
 
2. PK parameters such as trough concentrations can be derived from the concentration-
time data.  
 
Sample Required:. 
 
Maximum 30 ml blood and 10 ml urine at baseline, 3, 6, 9 and 12 months or early 
termination visit. Saliva is also being requested. Blood samples requested include 1 x 2 
ml ACD-A blood tube,  2 x-1ml serum samples 1 x 8.5ml CPT tube for PBMC collection 
Two (2) PAXgene RNA tubes, 5 ml EDTA tube.  
 
However, please note that we are minimizing the total amount of blood donation 
required for these studies by consolidating use of materials between BMS and 
Oklahoma scientific groups for different analyses, making more efficient use of available 
materials. 
 
REFERENCES  
 
1  Scarsi M, Ziglioli T, Airo P. Decreased circulating CD28-neagtive T cells in patients 
with rheumatoid arthritis treated with abatacept are correlated with clinical response. 
Journal of Rheumatology 37: 911-16, 2010. 
 

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2  Hoffman RW. T cells in the pathogenesis of systemic lupus erythematosus. Clinical 
Immunology 113: 2-13, 2004. 
3  Kyttaris VC, Juang Y-T. Tsokos GC. Immune cells and cytokines in systemic lupus 
erythematosus: an update. Current Opinion in Rheumatology 17(5): 518-522, 2005. 
4  Anand A, Dean GS, Quereshi K, Isenberg DA, Lydyard PM. Characterization of 
CD3+CD4-CD8- (double negative) T cells in patients with systemic lupus 
erythematosus: activation markers. Lupus 11: 493-500, 2002. 
5  Wong CK, Lit LCW, Tam LS, Li EK, Lam CWK. Aberrant production of soluble 
costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic 
lupus erythematosus. Rheumatology 44: 989-994, 2005. 
6  Gill MA, Blanco P, Arce E, Pascual V, Banchereau J, Palucka AK. Blood dendritic 
cells and DC-poietins in systemic lupus erythematosus. Human Immunology 63: 
1172-1180, 2002. 
7  Borschukova O, Paz Z, Ghiran IC, Liu C-C, Kao AH, Manzi S, Ahearn JM, Tsokos 
GC. Complement fragment C3d is colocalized within the lipid rafts of T cells and 
promotes cytokine production. Lupus 0: 1-11 2012. 
8  Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, Manku H, 
Vyse TJ, Roncador G, Huttley GA, Goodnow CC, Vinuesa CG, Cook MC. Expansion 
of circulating T cells resembling follicular helper T cells is a fixed phenotype that 
identifies a subset of severe systemic lupus erythematosus. Arthritis and 
Rheumatism 62(1): 234-244, 2010. 
 
APPENDIX 7: Repository 
 
In addition a small repository will be set aside to provide backup materials and to be 
able to make some materials available to other investigators in the future. Given the 
scope of studies already included in this protocol this repository will be quite modest. 
The informed consent will describe the currently planned ancillary studies and explain 
the purpose of the repository and patients will have the opportunity to give or withhold 
advance permission for use of their samples in future IRB-approved studies.  One 
Paxgene tube, sera, and EDTA for a total of 20cc blood as well as up to 20 cc urine and 
up to 5 cc saliva will be set aside in this repository.