1

Baricitinib for Systemic Lupus Erythematosus: Results from a Phase 2, Randomized,

Double-Blind, Placebo-Controlled Study

Daniel J Wallace, Richard A Furie, Yoshiya Tanaka, Kenneth C Kalunian, Marta Mosca,

Michelle A Petri, Thomas Dörner, Mario H Cardiel, Ian N Bruce, Elisa Gomez, Tara Carmack,

Amy M DeLozier, Jonathan M Janes, Matthew D Linnik, Stephanie de Bono, Maria E Silk,

Robert W Hoffman

Division of Rheumatology, Cedars-Sinai Medical Center/University California Los

Angeles, Los Angeles, CA, USA (Prof D Wallace MD);

Division of Rheumatology, Zucker School of Medicine at Hofstra/Northwell, New York,

NY, USA (Prof R Furie MD);

The First Department of Internal Medicine, School of Medicine, University of

Occupational and Environmental Health, Kitakyushu, Japan (Prof Y Tanaka MD);

Division of Rheumatology, University of California at San Diego School of Medicine, La

Jolla, CA, USA (Prof K Kalunian MD);

Division of Rheumatology, University of Pisa, Pisa, Italy (Prof M Mosca MD);

Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD,

USA (Prof M Petri MD);

Division of Rheumatology, Charite Universitätsmedizin Berlin, Berlin, Germany (Prof T

Dörner MD);

Centro de Investigación Clínica de Morelia SC, Morelia, México

(Prof M Cardiel MD);

Arthritis Research UK Centre for Epidemiology, Faculty of Biology, Medicine and Health,

The University of Manchester and NIHR Manchester Biomedical Research Centre,

Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health

Science Centre, Manchester, UK (Prof I Bruce MD);

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Lilly Biotechnology Center, San Diego, CA, USA (M Linnik PhD);

Eli Lilly and Company, Indianapolis, IN, USA (E Gomez MS, T Carmack MS, A DeLozier

MPH, J Janes MD, M Linnik PhD, S de Bono MD, M Silk PharmD, Prof R Hoffman, DO)

Correspondence to:

Prof Daniel J Wallace

Division of Rheumatology

Associate Director, Rheumatology Fellowship Program

Board of Governors, Cedars-Sinai Medical Center

Professor of Medicine, Cedars-Sinai Medical Center

David Geffen School of Medicine Center at UCLA

In affiliation with Attune Health

8750 Wilshire Blvd, Suite 350

Beverly Hills, CA 90211

Phone: (310) 652-0010

Fax: (310) 362-4812

danielwallac@gmail.com

Word count: 3521 of 4500 allowed

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Summary

Background: Patients with systemic lupus erythematosus (SLE) have substantial unmet

medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we

hypothesize may have therapeutic benefit in SLE.

Methods: In this double-blind, multicentre, randomized, placebo-controlled, 24-week, phase 2

study, patients were recruited from 78 centres across 11 countries. Patients were aged ≥18

years, had an SLE diagnosis, and active disease involving skin and/or joints. Patients were

randomly assigned (1:1:1) to receive baricitinib 4-mg, 2-mg, or placebo. The primary endpoint

was the proportion achieving resolution of arthritis or rash, as defined by SLEDAI-2K. This study

is registered with ClinicalTrials.gov, NCT02708095.

Findings: Between March 2016, to April 2017, 314 patients were randomly assigned to placebo

(n=105), baricitinib 2-mg (n=105), or baricitinib 4-mg (n=104). At week 24, a higher proportion of

patients achieved resolution of SLEDAI-2K arthritis or rash with baricitinib 4-mg (70 [67%]

patients; odds ratio vs placebo 1.8 [95% CI 1.0-3.3]; p=0.0414) and baricitinib 2-mg (61 [58%]

patients; odds ratio vs placebo 1.3 [95% CI 0.7-2.3]; p=0.39). A higher proportion of patients

attained the SRI-4 response at week 24 with baricitinib 4-mg (67 [64%] patients; odds ratio vs

placebo 2.0 [95% CI 1.2-3.6]; p=0.0151) and baricitinib 2-mg (54 [51%] patients; odds ratio vs

placebo 1.3 [95% CI 0.7-2.2]; p=0.44). Serious adverse events were reported in ten (10%)

patients with baricitinib 4-mg, eleven (10%) with baricitinib 2-mg, and five (5%) with placebo; no

deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4-mg,

two (2%) with baricitinib 2-mg, and one (1%) with placebo.

Interpretation: The 4-mg baricitinib dosing regimen improved the signs and symptoms of active

SLE in patients who were not adequately controlled despite standard of care therapy, with a

safety profile consistent with previous studies of baricitinib.

Funding: Eli Lilly and Company.

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Introduction

Systemic lupus erythematosus is a multi-system, chronic autoimmune disease characterized by

the presence of antibodies directed at self-antigens and broad immune dysregulation.1 It is

believed that abnormalities of both the innate and adaptive arms of the immune system,

interconnected by a positive feed forward loop, contribute to disease pathogenesis.2

Many key cytokines implicated in the pathogenesis of systemic lupus erythematosus are

dependent on activation of Janus kinases (JAKs) for intracellular signaling.1,3,4 The JAK family of

cytoplasmic protein tyrosine kinases mediates the signalling of a number of proinflammatory

cytokines, such as type l interferons (JAK1/tyrosine kinase [TYK] 2), interleukin (IL)-6

(JAK1/JAK2/TYK2), and IL-12 and IL-23 (JAK2/TYK2).3 Baricitinib is an orally administered

selective and reversible inhibitor of JAK1 and JAK25 that has been approved for the treatment of

moderately to severely active rheumatoid arthritis in adults in over 40 countries including

European countries and Japan. This molecular mechanism of action suggests that baricitinib

may inhibit cytokines central to the dysregulated innate and adaptive immune function observed

in systemic lupus erythematosus.

This global, phase 2, double-blind, placebo-controlled study was designed to assess the

efficacy, as well as safety and tolerability of oral baricitinib 2-mg or 4-mg once daily in patients

with active systemic lupus erythematosus receiving standard background therapy.

Methods

Study Design

In this randomized, double-blind, placebo-controlled, parallel-arm, 24-week, phase 2 trial, 79

investigators evaluated patients at 78 centres in 11 countries in Asia, Europe, North America,

and South America. The study protocol is available from the sponsor.

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Participants

Enrolled patients were 18 years of age or older and had been diagnosed with systemic lupus

erythematosus at least 24 weeks prior to screening by fulfilling 4 or more of the Revised

American College of Rheumatology (ACR) Criteria for Classification of Systemic Lupus

Erythematosus, or the 2012 Systemic Lupus Erythematosus International Collaborating Clinics

(SLICC) Classification Criteria.6-8 At baseline, patients were required to have a positive

antinuclear antibody (ANA) (HEp-2 ANA titre ≥1:80) and/or a positive anti-double-stranded

deoxyribonucleic acid (dsDNA) (≥30 IU, IgG INOVA QUANTA Lite SC ELISA), a Systemic

Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score of 4 or greater based on

clinical manifestations, and active arthritis or rash as defined by the SLEDAI-2K. Study drug was

added to existing stable background standard of care therapy, which could include non-steroidal

anti-inflammatory drugs (NSAID), corticosteroids, antimalarials (such as chloroquine,

hydroxychloroquine, or quinacrine) and/or immunosuppressants (such as azathioprine,

methotrexate, or mycophenolate). Corticosteroid dose was limited to ≤20-mg prednisone per

day (or equivalent) and was required to be stable for 2 weeks prior to randomization; increases

in dose were not permitted after randomization. Decreases in corticosteroid dose were

permitted from week 0 to week 16. No changes in corticosteroids were permitted between week

16 and week 24. No increases in antimalarials or immunosuppressants were allowed at any

time. Key exclusion criteria included active severe lupus nephritis, active severe central nervous

system lupus, recent clinically serious infection, and select laboratory abnormalities. Full

inclusion and exclusion criteria are provided in the Supplementary Appendix.

The study was conducted in accordance with ethical principles of the Declaration of Helsinki and

Good Clinical Practice guidelines. All investigation sites received approval from the appropriate

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authorized institutional review board or ethics committee. All patients provided written informed

consent before the study-related procedures were undertaken.

Randomization and Masking

Randomization was facilitated by a computer-generated random sequence with stratification

according to disease severity (SLEDAI-2K <10 or ≥10), anti-dsDNA status (positive or negative),

and region (United States, Europe, Asia, or rest of world) in a 1:1:1 ratio for placebo, baricitinib

2-mg or 4-mg, all administered orally. Treatment assignments were masked for patients and

investigators with daily doses provided at each visit in 2 bottles containing double-blind

investigational product tablets supplied by Eli Lilly and Company. Patients were instructed to

take 1 tablet from each bottle each day. Funder personnel remained masked until the week 24

analysis.

Procedures

Safety and efficacy outcomes were assessed on scheduled study visits (baseline, and weeks 2,

4, 8, 12, 16, 20, and 24) during the double-blind treatment period as indicated in the protocol

schedule of events. Patients were also assessed approximately 28 days after receiving their last

dose of study drug.

Outcomes

The primary objective was to compare the proportion of patients achieving resolution of arthritis

or rash, as defined by the SLEDAI-2K, when treated with baricitinib 4-mg or 2-mg compared to

placebo, at week 24.

Comparison of the proportion of patients achieving a Systemic Lupus Erythematosus

Responder Index-4 (SRI-4) response at week 24 for baricitinib versus placebo was a secondary

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objective. SRI-4 response is defined as: reduction of ≥4 points from baseline in SLEDAI-2K

score; no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG

B disease activity scores; and no worsening (defined as an increase of ≥0.3 points [10mm] from

baseline) in the Physician’s Global Assessment of Disease Activity (PGA). Other secondary

endpoints included comparisons of the proportion of patients achieving a reduction of ≥4 points

from baseline in SLEDAI-2K score, change in SLEDAI-2K total score, and change in PGA at

week 24 compared to baseline. Plasma baricitinib concentrations were also analysed using a

population pharmacokinetic (PK) approach. Exploratory assessments included 28-tender and

swollen joint counts, Cutaneous Lupus Erythematosus Disease Area and Severity Index

(CLASI) activity score, Safety of Estrogens in Lupus Erythematosus National Assessment

(SELENA)-SLEDAI Flare Index (SSFI), and SLICC/ACR Damage index. Corticosteroid doses

were recorded. Changes in serologic markers, including anti-dsDNA and complement

component (C) 3 and C4, were measured. Patient-reported outcomes assessed included Worst

Joint Pain NRS (numeric rating scale), Worst Pain NRS, and Worst Fatigue NRS (see Table S1

in Supplementary Appendix for description of instruments).

Safety

Clinical laboratory tests, vital signs, and other safety assessments were performed at scheduled

visits. Incidence and severity of all adverse events were recorded, and the Quick Inventory of

Depressive Symptomatology Self-Rated-16 was assessed. National Institutes of Health

Common Terminology Criteria for Adverse Events (CTCAE) was used to describe laboratory

abnormalities (version 4.03).

Statistical Analyses

With approximately 100 patients per treatment group, this study had approximately 81% power

to detect a difference of 20% between baricitinib 2-mg or 4-mg and placebo for the primary

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endpoint of resolution of arthritis or rash (SLEDAI-2K) at week 24. The expected treatment

difference was based on an expected overall placebo response rate of 40% and expected

baricitinib 2-mg or 4-mg response rate of 60%. This calculation was done with nQuery Advisor

7.0 two group chi-square test of equal proportions.

The primary, secondary, and exploratory endpoints were analysed according to the pre-

specified statistical analysis plan.

No multiplicity adjustment was employed in this phase 2 study. Efficacy and health outcomes

were analysed with the modified intention-to-treat population defined as all randomized patients

treated with ≥1 dose of study drug. Treatment comparisons of categorical efficacy endpoints

were made using logistic regression with treatment, region, baseline disease severity (SLEDAI-

2K <10 vs ≥10) and baseline anti-dsDNA status (positive or negative) in the model. Treatment

comparisons of continuous efficacy endpoints were made using pairwise comparisons in mixed

models repeated measures (MMRM) for outcomes with multiple post-baseline values or

analysis of covariance (ANCOVA) for outcomes with a single post-baseline value. The MMRM

model included treatment, baseline score, baseline disease severity (SLEDAI-2K <10 vs ≥10),

baseline anti-dsDNA status (positive or negative), region, visit, and the interaction of treatment-

by-visit as fixed factors. The ANCOVA model included treatment, baseline score, baseline

disease severity (SLEDAI-2K <10 vs ≥10), baseline anti-dsDNA status (positive or negative),

and region fitted as explanatory variables. Treatment comparisons for the time to first systemic

lupus erythematosus flare (SSFI) were made using a Cox proportional hazards model with

treatment group, baseline disease severity (SLEDAI-2K <10 vs ≥10), baseline anti-dsDNA

status (positive or negative), and region fitted as explanatory variables. Safety was assessed for

patients who received at least one dose of study drug and did not discontinue due to the reason

of ‘Lost to Follow-up’ prior to the first post-baseline visit. Adverse event and laboratory

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abnormality summaries included the treatment period and up to 30 or 60 days post-treatment,

respectively. The Fisher exact test was used for all adverse events, discontinuation, and other

categorical safety data. Continuous safety data were analysed using ANCOVA adjusting for

baseline value and treatment. Analyses were assessed at α=0.05 (2-sided).

For categorical efficacy analyses, patients were considered non-responders at each visit if they

a) were not responders at that visit, b) permanently discontinued study treatment at any time

prior to that visit for any reason, c) required initiation or increase in dose compared to baseline

of NSAIDs for 30 or more consecutive days, corticosteroids, antimalarials, or

immunosuppressants, after randomization, or d) had missing data at that visit. No imputation

was needed with MMRM for analysing the continuous efficacy endpoints. This study is

registered with ClincialTrials.gov, number NCT02708095.

Role of the Funding Source

This study was designed jointly by consultant experts and representatives of the funder, Eli Lilly

and Company. Data were collected by investigators and analysed by the funder. All authors

participated in data analysis and interpretation, draft and final manuscript review, and provided

critical comment, including the decision to submit the manuscript for publication with medical

writing support paid by the funder. The authors had full access to the data and verified the

veracity, accuracy, and completeness of the data and analyses as well as the fidelity of this

report to the protocol.

Results

Between March 2016 to April 2017, 314 patients were randomly assigned to receive once-daily

placebo (n=105), baricitinib 2-mg (n=105), or baricitinib 4-mg (n=104); 255 (81%) of these

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patients, completed the 24-week treatment period (Figure 1). No patients were excluded from

the efficacy and safety analyses.

Baseline demographics and disease activity were similar among groups (Table 1 and Table S2,

in the Supplementary Appendix). Ninety-four percent (n=294) patients were female and the

mean age at baseline was 44 years. At baseline, the mean duration of SLE was 11 years with a

mean SLICC/ACR index of 0.5. Patients had a baseline mean SLEDAI-2K score of 8.9, and

mean tender and swollen joint counts of 8.3 and 5.3, respectively. Patients had a mean baseline

CLASI index score of 4.2. The proportion of patients who met 1 A or 2 B BILAG scores was

60% (n=187). At baseline, 230 (73%), 222 (71%), and 142 (45%) patients were receiving

corticosteroids, antimalarials, or immunosuppressants, respectively.

The proportion of patients who achieved resolution of arthritis or rash (SLEDAI-2K), the primary

objective, was higher for patients who received baricitinib 4-mg (70 [67%] patients; odds ratio vs

placebo 1.8 [95% CI 1.0-3.3]; p=0.0414) (Figure 2 and Table 2). Improvement in the primary

outcome measure was also observed for baricitinib 2-mg (61 [58%] patients; odds ratio vs

placebo 1.3 [95% CI 0.7-2.3]; p=0.39), although the result was not statistically significant. Major

secondary endpoints were assessed. The proportion of patients achieving an SRI-4 response at

week 24 was higher for patients who received baricitinib 4-mg (67 [64%] patients; odds ratio vs

placebo 2.0 [95% CI 1.2-3.6]; p=0.0151); the result did not reach significance for baricitinib 2-mg

(54 [51%] patients; odds ratio vs placebo 1.3 [95% CI 0.7-2.2]; p=0.44) (Figure 2 and Table 2).

The achievement of an SRI-4 at week 24 was primarily driven by the SLEDAI-2K component

(baricitinib 4-mg: 67 [64%] patients; odds ratio vs placebo 2.0 [95% CI 1.1-3.5]; p=0.0220;

baricitinib 2-mg: 55 [52%] patients; odds ratio vs placebo 1.2 [95% CI 0.7-2.2]; p=0.45) (Table

2). The least squares mean change from baseline in PGA showed a significant decrease at

week 24 for patients who received baricitinib 4-mg (p=0.0218) versus placebo; results were not

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significant for the baricitinib 2-mg group (p=0.87) (Table 2 and Figure 2). PK/pharmacodynamic

(PD) models characterized the exposure response for SLEDAI-2K and SRI-4 across 24 weeks

of treatment and demonstrated that the majority of the patients had exposure at the plateau of

the curve (data not shown).

Improvements in exploratory outcomes including patient-reported outcomes were also observed

with baricitinib treatment. The proportion of patients who attained LLDAS with baricitinib 4-mg

was higher than that attained with placebo at week 24 (40 [38%] patients; odds ratio vs placebo

1.9 [95% CI 1.0-3.65; p=0.0391); the result did not reach significance for baricitinib 2-mg

(p=0.25) (Table 2). A lower risk of any flare as measured by the SSFI was observed for patients

receiving baricitinib 4-mg compared to placebo at week 24 (34 [33%] patients; hazard ratio vs

placebo 0.6 [95% CI 0.4-0.9; p=0.0193); the result did not reach significance for baricitinib 2-mg

(p=0.88). (Table 2 and Figure 3). Statistically significant improvements in tender joint count

(p=0.0377), Worst Joint Pain NRS (p=0.0157), and Worst Pain NRS (p=0.0403) were observed

with baricitinib 4-mg compared to placebo at week 24 (Table 2, Figure 3, and Figure S3, in the

Supplementary Appendix). Treatment with baricitinib 4-mg did not result in statistically

significant improvements at week 24 in other exploratory assessments evaluated. Results of the

exploratory analyses were not statistically significant for the baricitinib 2-mg group compared to

placebo at week 24, for most measures.

Rates of treatment discontinuation resulting from adverse events from baseline through week 24

were 4% (n=4), 10% (n=10), and 11% (n=11) for placebo, baricitinib 2-mg and 4-mg,

respectively (Table 3). Treatment-emergent adverse event rates were 65% (n=68), 71% (n=75),

and 73% (n=76) for placebo, baricitinib 2-mg and 4-mg, respectively (Table 3). Serious adverse

event rates were 5% (n=5) for placebo, and 10% for both baricitinib 2-mg (n=11) and 4-mg

(n=10) (Table 3 and Table S4, in the Supplementary Appendix). There were no deaths,

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malignancies, or major adverse cardiovascular events in the study (Table 3). One serious

adverse event of deep vein thrombosis was reported in the baricitinib 4-mg group, 46 days after

the patient’s first dose of baricitinib, in a patient with antiphospholipid antibodies (Table 3).

There were more serious infections reported in the baricitinib 4-mg group (6 [6%] patients) than

the 2-mg group (2 [2%] patients) or placebo group (1 [1%] patients) (Table 3 and Table S5, in

the Supplementary Appendix). There were no cases of serious or multidermatomal herpes

zoster, or opportunistic infection, and no reports of tuberculosis. There was 1 occurrence of non-

serious herpes zoster in the placebo group, none in the baricitinib 2-mg group, and 1 in the

baricitinib 4-mg group.

Table S6 (in the Supplementary Appendix) displays the mean change from baseline and

CTCAE grade increases for selected laboratory analytes through 24 weeks. There were modest

dose-associated decreases in haemoglobin and neutrophils. Early increases in lymphocytes

were observed with baricitinib treatment, but lymphocytes returned to baseline levels by week

24. There were modest dose-associated increases in platelet counts, creatine phosphokinase,

high-density lipoprotein cholesterol, total cholesterol, and triglycerides in the baricitinib groups.

No clinically meaningful differences in laboratory abnormalities were observed. Laboratory

changes were generally of low grade and consistent with changes observed for other

conditions,9-14 and four led to discontinuation of study drug.

DISCUSSION

The present study provides evidence that 4-mg daily oral baricitinib treatment of systemic lupus

erythematosus, in addition to standard of care therapy, was superior to placebo plus standard of

care in improving signs and symptoms of active systemic lupus erythematosus.

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The primary objective, resolution of arthritis or rash by SLEDAI-2K, was selected for this phase

2 trial as arthritis and rash are among the most common manifestations of systemic lupus

erythematosus and are the two most frequent clinical manifestations at entry in recent clinical

trials of extra-renal systemic lupus erythematosus. The SLEDAI-2K organ domain scoring is a

validated, widely used outcome measure for the study of systemic lupus erythmatosus.15,16

Arthritis, as well as musculoskeletal pain, is a prominent symptom of systemic lupus

erythematosus patients, and improvement in musculoskeletal symptoms have significantly

correlated with improvement in quality of life using several measures.17-20 Baricitinib

demonstrated, by physician assessment, improvement in the proportion of patients with arthritis,

as measured using the SLEDAI-2K arthritis organ domain score, and improvement in the

proportion with joint tenderness, as measured by 28-joint examination. Baricitinib 4-mg also

demonstrated, measured using patient-reported outcomes, reduction in the proportion of

patients with worst joint pain and global pain when compared to placebo. In this phase 2 study,

it was also important to benchmark improvement using an established composite endpoint, the

SRI-4, which assesses overall disease activity improvement using a global disease index. The

SRI-4 is a validated, widely accepted clinical trial and global regulatory endpoint for studies of

systemic lupus erythematosus.21 Additional results supporting the results on the primary

endpoint were the statistically significant improvements in SRI-4, as well as other important

general measures of disease activity including PGA, LLDAS, SSFI flares, and patient-reported

outcomes with baricitinib 4-mg. Baricitinib 2-mg did not show any statistically significant

differences from placebo across the primary and secondary efficacy objectives studied at week

24, although improvements compared to placebo were observed.

There were no statistically significant improvements in the signs or symptoms of skin disease in

this study whether measured using proportions of patients meeting the SLEDAI-2K

mucocutaneous organ domain score or using the CLASI activity score for severity when

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comparing placebo with baricitinib 2-mg or 4-mg. Although the percentage of patients with

mucocutaneous disease activity measured by SLEDAI-2K was high (84%), the overall activity

score for severity at entry, as measured by CLASI, was low. Currently, there is limited data on

the use of CLASI in phase 2 or 3 clinical trials in SLE; hence, the utility of CLASI remains

uncertain. A mean baseline CLASI activity score of 4.2, as seen here, may be inadequate to

discern a difference between placebo and treatment with baricitinib 2-mg or 4-mg daily, and the

study was not powered to observe small changes in CLASI. Notably, however, JAK inhibitors

have been reported to have positive effects on skin in several dermatologic conditions including

atopic dermatitis, psoriasis, graft versus host disease, and alopecia areata and there remains

reason to anticipate JAK inhibitors may have potential efficacy in treating the mucocutaneous

features of SLE.3,13,14,22

The safety profile of baricitinib in patients with active systemic lupus erythematosus receiving

standard of care treatment was consistent with published findings in patients receiving baricitinib

in other studies. No notable safety observations emerged compared to the results from studies

of baricitinib for other conditions.9-14 Baricitinib treatment was associated with a higher proportion

of patients that discontinued study treatment due to adverse events compared to placebo.

Serious adverse events were more frequent with baricitinib treatment compared to placebo.

However, in this study, serious infection rates were more frequent with baricitinib 4-mg than

baricitinib 2-mg and placebo. The serious infection rate of 6% seen here with baricitinib 4-mg

was similar to that reported in other trials such as those for belimumab, which reported 5% for

the placebo plus standard of care arm and 6% for belimumab.23 The rate of serious infections

may be affected by the frequent usage of potent immune modifying standard of care medication

as background therapy. There were no reports of death, malignancies, major adverse

cardiovascular events, tuberculosis, or serious herpes zoster.

15

The occurrence of thrombosis with JAK inhibition is an area of increased attention and debate.

There was a single episode of deep vein thrombosis in the present study, which occurred in a

patient receiving baricitinib 4-mg, and who was positive for antiphospholipid antibodies. It is

noteworthy that only one event was observed in the trial despite a study population in which

nearly 30% of patients had antiphospholipid antibodies. There was no exclusion from the study

on the basis of risk factors, including prior history of thrombosis (unless the occurrence was

recent, namely within the previous 24 weeks).

While no clinically meaningful differences in laboratory abnormalities were observed, baricitinib

treatment resulted in modest dose-associated decreases in haemoglobin levels and neutrophil

counts, and increases in platelet counts and levels of creatine phosphokinase, high-density

lipoprotein cholesterol, total cholesterol, and triglycerides.

There are limitations to the conclusions that can be drawn from this study. Notably, this trial is

among few other phase 2 studies that have demonstrated a positive outcome within 24-

weeks,24,25 however this timeframe limited the ability to assess long-term outcomes and

damage. Further improvements in efficacy may be seen in a 52-week study. Patients were

allowed to continue existing stable background standard of care therapy, including

corticosteroids, and while baseline standard of care use was balanced across groups,

background therapy could potentially confound the results and contribute to the high placebo

response rate. This is a recurring issue in lupus trials,26 but despite this confounder, the results

were positive.

In summary, despite treatment advances, systemic lupus erythematosus remains a disease with

an unacceptable morbidity and mortality.27 Existing treatments can be associated with

incomplete efficacy or significant toxicity.28 Since baricitinib has selectivity for JAK1 and JAK2,5 it

16

may inhibit pathways that have been implicated as central to the pathogenesis of systemic lupus

erythematosus, and we hypothesized that baricitinib could have clinical benefit in active

systemic lupus erythematosus. In this phase 2 study in patients with systemic lupus

erythematosus receiving standard background therapy, once-daily baricitinib 4-mg was

associated with significant clinical improvements compared to placebo. Baricitinib treatment was

not associated with any notable safety findings compared to results from baricitinib studies for

other conditions.9-14 These findings support further study of baricitinib as a potential therapy for

patients with systemic lupus erythematosus.

17

Contributors

All authors contributed to the concept and design of the study, contributed to data analysis and

interpretation, critical revision of the publication, final approval to submit, and were accountable

for the accuracy and integrity of the publication.

Declaration of Interests

Daniel J. Wallace has received consulting support from Amgen, Eli Lilly and Company, EMD

Merck Serono, and Pfizer. Richard A. Furie has received consulting support from Eli Lilly and

Company. Yoshiya Tanaka has received grant/research support or speaker bureau fees from

AbbVie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, Janssen, Kyowa-

Kirin, Mitsubishi-Tanabe, MSD, Ono, Pfizer, Takeda, Sanofi, UCB, and YL Biologics. Kenneth

C. Kalunian has received consulting support from Eli Lilly and Company. Marta Mosca has

received consulting support from Eli Lilly and Company. Michelle A. Petri has received

consulting support from Eli Lilly and Company. Thomas Dörner has received grant/research

support, consulting support, or speaker bureau fees from AbbVie, Biogen, Celgene, Chugai, Eli

Lilly and Company, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB. Mario H. Cardiel

has received grant/research support, consulting support, or speaker bureau fees from AbbVie,

Eli Lilly and Company, Gilead, Janssen, Pfizer, and Roche. Ian N. Bruce has received

grant/research support, consulting support, or speaker bureau fees from Astra Zeneca, BMS, Eli

Lilly and Company, Genzyme, GSK, Merck Serono, and UCB. Elisa Gomez, Amy M. DeLozier,

Jonathan M. Janes, Matthew D. Linnik, Stephanie de Bono, Maria T. Silk, and Robert W.

Hoffman are employees and stockholders of Eli Lilly and Company. Tara Carmack is an

employee of Eli Lilly and Company.

Acknowledgements

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The authors would like to thank the patients who participated in the study, Nicole Byers, PhD of

Eli Lilly and Company for assisting with manuscript preparation and process support, and Julie

Sherman, AAS of Eli Lilly and Company for figure assistance. Prof. Bruce is a National Institute

for Health Research (NIHR) Senior Investigator and is supported by the NIHR Manchester

Biomedical Research Centre. The views expressed in this publication are those of the author(s)

and not necessarily those of the NHS, the National Institute for Health Research or the

Department of Health.

References

1. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 2016; 12(12): 716-30.2. Wahren-Herlenius M, Dorner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013; 382(9894): 819-31.3. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017; 16(12): 843-62.4. Hoffman RW, Merrill JT, Alarcon-Riquelme MM, et al. Gene expression and pharmacodynamic changes in 1,760 systemic lupus erythematosus patients from two phase III trials of BAFF blockade with tabalumab. Arthritis Rheumatol 2017; 69(3): 643-54.5. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 2010; 184(9): 5298-307.6. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25(11): 1271-7.7. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40(9): 1725.8. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64(8): 2677-86.9. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016; 374(13): 1243-52.10. Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017; 76(1): 88-95.11. Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 2017; 69(3): 506-17.12. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017; 376(7): 652-62.

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13. Guttman-Yassky E, Silverberg JI, Nemoto O, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol 2018.14. Papp KA, Menter MA, Raman M, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol 2016; 174(6): 1266-76.15. Manzi S, Sanchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 2012; 71(11): 1833-8.16. Kalunian KC, Urowitz MB, Isenberg D, et al. Clinical trial parameters that influence outcomes in lupus trials that use the systemic lupus erythematosus responder index. Rheumatology (Oxford) 2018; 57(1): 125-33.17. Urowitz M, Gladman DD, Ibanez D, et al. Changes in quality of life in the first 5 years of disease in a multicenter cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2014; 66(9): 1374-9.18. Urowitz MB, Gladman DD, Ibanez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken) 2012; 64(1): 132-7.19. Jolly M, Pickard AS, Block JA, et al. Disease-specific patient reported outcome tools for systemic lupus erythematosus. Semin Arthritis Rheum 2012; 42(1): 56-65.20. Moorthy LN, Baldino ME, Kurra V, et al. Relationship between health-related quality of life, disease activity and disease damage in a prospective international multicenter cohort of childhood onset systemic lupus erythematosus patients. Lupus 2017; 26(3): 255-65.21. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009; 61(9): 1143-51.22. MacDonald KPA, Betts BC, Couriel D. Emerging Therapeutics for the Control of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 2018; 24(1): 19-26.23. GlaxoSmithKline. Belimumab prescribing information 2017. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU-COMBINED.PDF (accessed May 31, 2018.24. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis 2014; 73(1): 183-90.25. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol 2017; 69(2): 376-86.26. Merrill JT, Manzi S, Aranow C, et al. Lupus community panel proposals for optimising clinical trials: 2018. Lupus Science &amp; Medicine 2018; 5(1).27. Yurkovich M, Vostretsova K, Chen W, Avina-Zubieta JA. Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies. Arthritis Care Res (Hoboken) 2014; 66(4): 608-16.28. Thong B, Olsen NJ. Systemic lupus erythematosus diagnosis and management. Rheumatology (Oxford) 2017; 56(suppl_1): i3-i13.

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Research in context

Evidence before this study

PubMed was searched using the terms “systemic lupus erythematosus”, “treatment”, and “JAK inhibitor” for English language publications published up to March 1, 2016, regardless of article type. The authors considered previous clinical trials of investigational medication in systemic lupus erythematosus (SLE) as well as previous clinical trials of the Janus kinase (JAK)1/2 inhibitor, baricitinib, prior to undertaking this study. Current treatment regimens for the management of SLE have resulted in a reduction of morbidity and mortality over previous decades, however, many patients still have incompletely controlled disease and can progress to end-stage organ involvement. There are a limited number of medications approved for the treatment of SLE and other medications are used off-label; collectively, these include antimalarials, non-steroidal anti-inflammatory drugs (NSAID), aspirin, corticosteroids, azathioprine, mycophenolate, cyclophosphamide, methotrexate, belimumab and rituximab. Due to their limited efficacy these drugs are often use in multiple combinations, rather than as single agents, resulting in added toxicity. New treatment options with an acceptable safety profile that reduce disease activity, reduce flares, delay organ damage, and reduce the requirement for corticosteroids and cytotoxic agents are urgently needed for patients with SLE. In addition, the need for treatments that improve quality of life, including control of pain and fatigue, has been articulated by patients as well as physicians. Clinical and laboratory studies have demonstrated a central role for JAK/signal transducer and activator of transcription (STAT) in cytokine-mediated immune signaling and inflammation. This includes JAK/STAT-mediated signaling through type-1 interferons, which have previously been demonstrated to have an important role in the pathogenesis of SLE. In this phase 2 trial, a JAK1/2 inhibitor, baricitinib, improved signs and symptoms in patients with active SLE.

Added value of this study

In this phase 2 trial of baricitinib in the treatment of patients with active SLE receiving standard background therapy, baricitinib improved the signs and symptoms of active disease. Baricitinib 4-mg treatment resulted in a greater proportion of patients achieving SLEDAI-2K-defined resolution of arthritis compared to placebo, and a greater proportion achieving the composite SRI-4 endpoint at week 24 compared to placebo. The safety profile of baricitinib was consistent with other agents used to treat active SLE.

Implication of all the available evidence

These findings support the evidence that JAK/STAT signaling may have a central role in the pathogenesis of SLE. This is the first study demonstrating clinical benefit of JAK inhibition in the treatment of SLE. This work provides the foundation for additional study of JAK1/2 inhibition with baricitinib in SLE as a potentially effective oral treatment option for active SLE in patients who have not achieved adequate disease control with available standard of care therapies.

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FIGURE LEGENDS

Figure 1. Trial Profile

Figure 2. Primary and Secondary Efficacy Analyses.

The percentage of patients achieving resolution of arthritis or rash, determined by the SLEDAI-

2K, is shown in Panel A. The percentage of patients achieving an SRI-4 response is shown in

Panel B. Panel C shows the least squares mean (LSM) change from baseline in the SLEDAI-2K

score (scores ranging from 0 to 105, higher scores indicate more severe disease). The LSM

change from baseline in the Physician’s Global Assessment of Disease Activity with scores

ranging from 0 (0 mm) to 3 (100 mm) (visual analog scale, higher scores indicate more severe

disease) is shown in panel D. Panels A-D include all patients in the modified intention-to-treat

analysis set (all randomized and treated patients), which included 314 patients. p values for

comparisons between baricitinib 2-mg or 4-mg with placebo are shown.

Figure 3. Improvements in Systemic Lupus Erythematosus Disease Activity through

Week 24.

The least squares mean (LSM) change from baseline in tender joint count and swollen joint

count are shown in Panels A and B, respectively. Panels C and D show the time to first flare of

any severity and the time to first severe flare, as defined by the SELENA-SLEDAI Flare Index,

respectively. p values for comparisons between baricitinib 2-mg or 4-mg with placebo are

shown.

22

Table 1. Baseline Characteristics and Disease Activity*

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Age (years) 44.9 (12.8) 43.2 (11.0) 45.0 (12.4)

Time since onset of SLE (years) 9.7 (7.7) 11.8 (9.1) 11.5 (10.3)

Concomitant medications

Corticosteroids 77 (73%) 79 (75%) 74 (71%)

Prednisone dose [or equivalent] (mg/day) 7.9 (4.6) 8.7 (5.8) 10.5 (17.4)

Prednisone dose [or equivalent] ≥7.5 mg/day 36 (47%) 40 (51%) 41 (55%)

Antimalarials 75 (71%) 71 (68%) 76 (73%)

Immunosuppressants 45 (43%) 47 (45%) 50 (48%)

MTX 13 (12%) 17 (16%) 13 (13%)

AZA 15 (14%) 10 (10%) 11 (11%)

MMF 11 (10%) 10 (10%) 16 (15%)

NSAID 27 (26%) 29 (28%) 32 (31%)

SLEDAI-2K score† 8.9 (2.9) 8.8 (3.4) 9.0 (3.3)

SLEDAI-2K ≥10 43 (41%) 35 (33%) 44 (42%)

SLEDAI-2K organ system involvement

CNS 3 (3%) 1 (1%) 2 (2%)

Vascular 1 (1%) 4 (4%) 3 (3%)

Musculoskeletal 93 (89%) 93 (89%) 96 (92%)

Renal 9 (9%) 9 (9%) 7 (7%)

Mucocutaneous 90 (86%) 82 (78%) 92 (88%)

Cardiovascular and respiratory 2 (2%) 1 (1%) 1 (1%)

Immunologic 62 (59%) 63 (60%) 64 (62%)

Constitutional 2 (2%) 2 (2%) 0

23

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Hematologic 13 (12%) 9 (9%) 5 (5%)

≥1 A or ≥2 B BILAG scores‡ 62 (59%) 56 (53%) 69 (66%)

Physician’s Global Assessment§ 49.5 (16.9) 48.8 (15.8) 51.7 (16.0)

CLASI activity score¶ 4.9 (5.7) 3.8 (5.4) 4.0 (3.4)

Tender joint count 7.7 (5.8) 8.7 (6.6) 8.5 (6.2)

Swollen joint count 5.3 (4.7) 5.2 (4.7) 5.5 (4.2)

SLICC/ACR Damage Index scoreǁ 0.59 (0.97) 0.44 (0.68) 0.40 (0.88)

Data are mean (SD) or n (%). ACR=American College of Rheumatology. AZA=azathioprine.

BILAG=British Isles Lupus Assessment Group. CLASI=Cutaneous Lupus Erythematosus

Disease Area and Severity Index. CNS=central nervous system. MMF=mycophenolate mofetil.

MTX=methotrexate. N=number of patients randomized and treated. n=number of patients in the

specified category. NSAID=nonsteroidal anti-inflammatory drug. SD=standard deviation.

SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index-2000. SLICC=Systemic

Lupus International Collaborating Clinics. *Additional baseline characteristics and disease

activity are described in Table S2, in the Supplementary Appendix. †Scores range from 0 to

105, with higher values indicating more severe disease. ‡A score indicates severe disease and

B score indicates moderate disease. §Scores range from 0 (0 mm) to 3 (100 mm) (visual analog

scale), with higher values indicating more severe disease. ¶Scores range from 0 to 70, with

higher values indicating more severity. ǁScores range from 0 to 45, with higher values indicating

more damage.

24

Table 2. Clinical and Biomarker Outcomes at Week 24

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Week 24 Week 24 p value* Comparison

vs placebo

(95% CI)

Week 24 p value* Comparison

vs placebo

(95% CI)

Proportion of patients who had a

response†

Resolution of arthritis/rash

(SLEDAI-2K)

56 (53%) 61 (58%) 0.39 1.3 (0.7 to 2.3) 70 (67%) 0.0414 1.8 (1.0 to 3.3)

SRI-4 50 (48%) 54 (51%) 0.44 1.3 (0.7 to 2.2) 67 (64%) 0.0151 2.0 (1.2 to 3.6)

≥4 point improvement in

SLEDAI-2K

51 (49%) 55 (52%) 0.45 1.2 (0.7 to 2.2) 67 (64%) 0.0220 2.0 (1.1 to 3.5)

No worsening (≥1A/2B) by

BILAG

80 (76%) 82 (78%) 0.67 1.2 (0.6 to 2.2) 85 (82%) 0.31 1.4 (0.7 to 2.8)

No worsening by PGA 78 (74%) 82 (78%) 0.45 1.3 (0.7 to 2.5) 84 (81%) 0.26 1.5 (0.8 to 2.9)

25

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Week 24 Week 24 p value* Comparison

vs placebo

(95% CI)

Week 24 p value* Comparison

vs placebo

(95% CI)

LLDAS 27 (26%) 35 (33%) 0.25 1.4 (0.8 to 2.7) 40 (38%) 0.0391 1.9 (1.0 to 3.5

Flares (any severity) on the

SELENA-SLEDAI Flare Index‡

54 (51%) 45 (43%) 0.88 1.0 (0.6 to 1.5) 34 (33%) 0.0193 0.6 (0.4 to 0.9)

Severe flares on the SELENA-

SLEDAI Flare Index‡

12 (11%) 10 (10%) 0.98 1.0 (0.4 to 2.3) 6 (6%) 0.17 0.5 (0.2 to 1.3)

Least squares mean change from

baseline§

SLEDAI-2K -3.8 (0.4) -4.1 (0.4) 0.60 -0.3 (-1.2 to 0.7) -4.4 (0.4) 0.24 -0.6 (-1.6 to 0.4)

Physician’s Global Assessment -26.3

(1.8)

-25.9

(1.8)

0.87 0.4 (-4.6 to 5.4) -32.2 (1.8) 0.0218 -5.9 (-10.9 to -0.9)

CLASI activity score -2.8 (0.4) -1.7 (0.4) 0.0371 1.1 (0.1 to 2.2) -2.3 (0.4) 0.33 0.5 (-0.5 to 1.6)

26

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Week 24 Week 24 p value* Comparison

vs placebo

(95% CI)

Week 24 p value* Comparison

vs placebo

(95% CI)

Tender joint count -5.6 (0.4) -6.5 (0.4) 0.13 -0.9 (-2.1 to 0.3) -6.9 (0.4) 0.0377 -1.3 (-2.5 to -0.1)

Swollen joint count -4.6 (0.2) -4.1 (0.2) 0.14 0.5 (-0.2 to 1.1) -4.8 (0.2) 0.60 -0.2 (-0.8 to 0.5)

SLICC/ACR Damage Index score 0.05

(0.03)

0.07

(0.03)

0.53 0.03 (-0.05 to

0.10)

0.07 (0.03) 0.52 0 .03 (-0.05 to 0.10)

Worst Joint Pain NRS -0.9 (0.3) -1.6 (0.3) 0.07 -0.6 (-1.3 to 0.1) -1.8 (0.3) 0.0157 -0.9 (-1.6 to -0.2)

Worst Pain NRS -0.6 (0.3) -1.2 (0.3) 0.10 -0.6 (-1.3 to 0.1) -1.3 (0.3) 0.0403 -0.8 (-1.5 to 0)

Worst Fatigue NRS -1.2 (0.2) -1.1 (0.2) 0.89 0.1 (-0.6 to 0.7) -1.5 (0.2) 0.32 -0.3 (-1.0 to 0.3)

Anti-dsDNA, IU/mL 55.4

(26.8)

1.0 (27.1) 0.15 -54.4 (-128.0 to

19.2)

48.5 (26.9) 0.86 -6.8 (-80.6 to 66.9)

Complement C3, g/L 0 (0.02) 0 (0.02) 0.75 -0.01 (-0.06 to

0.04)

-0.02 (0.02) 0.31 -0.02 (-0.07 to 0.02)

Complement C4, g/L 0.01

(0.01)

-0.01

(0.01)

0.18 -0.01 (-0.03 to 0) -0.01 (0.01) 0.0314 -0.02 (-0.03 to 0)

27

Data are least squares mean (SE) or n (%). Data were analysed with a logistic regression model with non-responder imputation for

response rates, mixed-models repeated-measure analysis or ANCOVA for least squares mean change from baseline, and Cox

proportional hazard model for time to event. ACR=American College of Rheumatology. BILAG=British Isles Lupus Assessment

Group. CI=confidence interval. CLASI=Cutaneous Lupus Erythematosus Disease Area and Severity Index. dsDNA=double-stranded

deoxyribonucleic acid. HR=hazard ratio. LLDAS=Lupus Low Disease Activity State. LSM=least squares mean. N=number of patients

randomized and treated. n=number of patients in the specified category. PGA=Physician’s Global Assessment of Disease Activity.

SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index-2000. SLICC=Systemic Lupus International Collaborating

Clinics. SRI-4=Systemic Lupus Erythematosus Responder Index-4. *p value in comparison to placebo. †Comparison reported as

odds ratio. ‡Comparison reported as hazard ratio for time to event. §Comparison reported as least squares mean difference.

28

Table 3. Safety Summary, Weeks 0-24 and up to 30 Days Post-Treatment

Placebo

(N=105)

Baricitinib 2-mg

(N=105)

Baricitinib 4-mg

(N=104)

Discontinuation from study treatment due to adverse

event4 (4%) 10 (10%) 11 (11%)

Any adverse event after the start of therapy 68 (65%) 75 (71%) 76 (73%)

Serious adverse events 5 (5%) 11 (10%) 10 (10%)

Infections 41 (39%) 47 (45%) 47 (45%)

Serious infections 1 (1%) 2 (2%) 6 (6%)

Herpes zoster 1 (1%) 0 1 (1%)

Tuberculosis 0* 0 0

Malignancies 0 0 0

Major adverse cardiovascular events† 0 0 0

Deep vein thrombosis 0 0 1 (1%)

Death 0 0 0

Data are n (%). N=number of patients in the analysis population. n=number of patients in the

specified category. *One patient with latent tuberculosis (based on a positive QuantiFERON-TB

Gold test result after randomization). †Non-adjudicated.

29

Figure 1. Trial Profile

30

Figure 2. Primary and Secondary Efficacy Analyses

31

Figure 3. Improvements in Systemic Lupus Erythematosus Disease Activity through

Week 24