Articles
Baricitinib for systemic lupus erythematosus: a double-blind,
Lancet 2018; 392: 222–31
See Comment page 190
Division of Rheumatology,
Cedars-Sinai Medical Center,
University of California at
Los Angeles, Los Angeles, CA,
USA (Prof D J Wallace MD);
Division of Rheumatology,
Zucker School of Medicine at
Hofstra, Northwell, New York,
NY, USA (Prof R A 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 C 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 A 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 H 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 N Bruce MD); Lilly
Biotechnology Center,
San Diego, CA, USA
(M D Linnik PhD); and Eli Lilly
and Company, Indianapolis, IN,
USA (E Gomez MS,
T Carmack MS,
A M DeLozier MPH,
J M Janes MD, S de Bono MD,
M E Silk PharmD,
Prof R W Hoffman, DO)
222 www.thelancet.com Vol 392 July 21, 2018
randomised, placebo-controlled, phase 2 trial
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
Summary
Background Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral
selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with
systemic lupus erythematosus.
Methods In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were
recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic
lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive
once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of
patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease
Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of
study drug. This study is registered with ClinicalTrials.gov, number NCT02708095.
Findings Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo
(n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash
was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0–3·3;
p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7–2·3; p=0·39). Adverse events were
reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%)
patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving
baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving 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 baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of
active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy,
with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future
phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus.
Funding Eli Lilly and Company.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction which has been approved for the treatment of moderately
Systemic lupus erythematosus is a multisystem, chronic to severely active rheumatoid arthritis in adults in over
autoimmune disease characterised by the presence of 40 countries, including European countries, the USA,
antibodies directed at self-antigens, and broad immune and Japan. This molecular mechanism of action suggests
dysregulation.1 It is believed that abnormalities of both that baricitinib might inhibit cytokines central to the
the innate and adaptive arms of the immune system, dysregulated innate and adaptive immune function
interconnected by a positive feedback loop, contribute to observed in systemic lupus erythematosus.
disease pathogenesis.2 We designed this international, double-blind, random­
ised, placebo-controlled, phase 2 trial to assess the
Many key cytokines implicated in the pathogenesis
of systemic lupus erythematosus are dependent on efficacy, safety, and tolerability of oral baricitinib (2 mg or
activation of Janus kinases (JAKs) for intracellular 4 mg) once-daily in patients with active systemic lupus
signalling.1,3,4 The JAK family of cytoplasmic protein erythematosus, who were receiving standard background
tyrosine kinases mediates the signalling of several therapy.
pro-inflammatory cytokines, such as type l inter­
ferons (JAK1/tyrosine kinase [TYK] 2), interleukin 6 Methods
(JAK1/JAK2/TYK2), and interleukin 12 and interleukin 23 Study design and participants
(JAK2/TYK2).3 Baricitinib is an orally administered In this double-blind, randomised, placebo-controlled
selective and reversible inhibitor of JAK1 and JAK2,5 trial, 79 investigators assessed patients at 78 centres in

Research in context
Evidence before this study
We searched PubMed using the terms “systemic lupus
erythematosus”, “treatment”, and “JAK inhibitor” for articles in
English published up to March 1, 2016, regardless of article
type. We considered previous clinical trials of investigational
medication in systemic lupus erythematosus, as well as
previous clinical trials of the Janus kinase (JAK)1/2 inhibitor,
baricitinib, before doing this study. Current treatment
regimens for the management of systemic lupus
erythematosus 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 small number of
medications approved for the treatment of systemic lupus
erythematosus and other medications are used off-label;
collectively, these include antimalarials, non-steroidal
anti-inflammatory drugs, aspirin, corticosteroids, azathioprine,
mycophenolate, cyclophosphamide, methotrexate,
belimumab, and rituximab. Because of their limited efficacy,
these drugs are often used in multiple combinations, rather
than as single agents, resulting in added risk of 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 drugs are
urgently needed for patients with systemic lupus
erythematosus. Additionally, the need for treatments that
improve quality of life, including control of pain and fatigue,
has been articulated by patients and physicians. Clinical and
laboratory studies have showed a central role for JAK and
11 countries in Asia, Europe, North America, and South
America. The study protocol is available from the
sponsor.
Eligible participants were 18 years or older and had
been diagnosed with systemic lupus erythematosus
at least 24 weeks before screening by fulfilling four
or more of the revised American College of Rheumatology
(ACR) criteria for classification of sys­temic lupus erythe­
matosus, 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 (HEp-2 titre ≥1:80), a
positive anti-double-stranded DNA (anti-dsDNA;
≥30 IU/mL), IgG INOVA QUANTA Lite SC ELISA
(INOVA Diagnostics, San Diego, CA, USA), a Systemic
Lupus Erythematosus Disease Activity Index-2000
(SLEDAI-2K) score of 4 or greater based on clinical
manifestations, or active arthritis or rash as defined by
the SLEDAI-2K. Study drug was added to existing
stable background standard of care ther­apy, which could
be non-steroidal anti-inflam­matory drugs, corticosteroids,
a single antimalarial (such as chloroquine or hydroxy­
chloroquine), or a single immuno­ suppressant (such
as azathioprine, metho­trexate, or mycophenolate). The
www.thelancet.com Vol 392 July 21, 2018 223
Articles
Correspondence to:
Prof Daniel J Wallace, Division of
Rheumatology, Cedars-Sinai
signal transducer and activator of transcription (STAT) in Medical Center, Los Angeles, CA
cytokine-mediated immune signalling and inflammation. This 90048, USA
pathway includes JAK/STAT-mediated signalling through danielwallac@gmail.com
type 1 interferons, which have been shown to have an
important role in the pathogenesis of systemic lupus
erythematosus.
Added value of this study
In this phase 2 trial, baricitinib improved the signs and
symptoms of active disease in patients with systemic lupus
erythematosus who were receiving standard background
therapy. Baricitinib 4 mg treatment resulted in a greater
proportion of patients achieving resolution of arthritis, as
defined by Systemic Lupus Erythematosus Disease Activity
Index-2000, than with placebo. The safety profile of baricitinib
was consistent with other drugs used to treat active systemic
lupus erythematosus.
Implications of all the available evidence
These findings support the evidence that JAK/STAT signalling
could have a central role in the pathogenesis of systemic
lupus erythematosus. To our knowledge, this is the first study
to show clinical benefit of JAK inhibition in the treatment of
systemic lupus erythematosus. This work provides the
foundation for additional study of JAK1/2 inhibition with
baricitinib as a potentially effective oral treatment option for
active systemic lupus erythematosus in patients who have
not achieved adequate disease control with available
standard of care therapies.
corticosteroid dose was limited to 20 mg or less of
prednisone per day (or equivalent), and was required to
be stable for 2 weeks before randomisation; increases in
dose were not permitted after randomisation. Decreases
in cor­ticosteroid dose were permitted from baseline to
week 16. No changes in corticosteroid dose 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 CNS lupus, recent
clinically serious infection, and selected laboratory
abnormalities. A full list of exclusion criteria are shown
in the appendix. See Online for appendix
The study was done in accordance with the ethical
principles of the Declaration of Helsinki and Good
Clinical Practice guidelines. All investigation sites
received approval from the appropriate authorised
institutional review board or ethics committee. All
patients provided written informed consent before the
study-related procedures were done.
Randomisation and masking
We used a computer-generated random sequence to
allocate patients (1:1:1) to placebo, baricitinib 2 mg, or
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baricitinib 4 mg. Patients were stratified according to
disease severity (SLEDAI-2K score <10 or ≥10), anti-
dsDNA status (positive or negative), and region (USA,
Europe, Asia, or rest of world). Patients and investigators
were masked to allocation. Daily doses were provided
at each visit in two bottles containing identical
investigational product tablets supplied by Eli Lilly and
Company. All study investigators remained masked until
the week 24 analysis.
Procedures
All interventions were given orally. Patients were
instructed to take one tablet from each bottle each day
(one tablet of placebo, one tablet of study drug). Safety
outcomes (clinical laboratory tests, vital signs, and other
safety assessments) 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 outcome was the proportion of patients
achieving resolution of arthritis or rash, as defined by the
SLEDAI-2K, at week 24.
The proportion of patients achieving a Systemic
Lupus Erythematosus Responder Index-4 (SRI-4)
response at week 24 was a secondary objective. SRI-4
response is defined as a reduction of at least 4 points
from baseline in SLEDAI-2K score, no worsening in
British Isles Lupus Assessment Group (BILAG) A or B
414 patients screened
disease activity scores (no new BILAG A score or no
more than one new BILAG B score), and no worsening
(defined as an increase of ≥0·3 points [10 mm] from
baseline) in the Physician’s Global Assessment of
Disease Activity (PGA). Other secondary endpoints
were the proportion of patients achieving a reduction
of 4 points or more from baseline in SLEDAI-2K score,
and change from baseline in SLEDAI-2K total score
and PGA at week 24. We analysed plasma baricitinib
concen­trations using a population pharmaco­ kinetic
approach, to characterise the exposure response for
SLEDAI-2K and SRI-4 across 24 weeks (data not
shown). Exploratory assessments were change from
baseline in 28-tender joint count and 28-swollen joint
count, Cutaneous Lupus Erythematosus Disease
Area and Severity Index (CLASI) activity score, and
SLICC/ACR Damage index; risk of flares of any severity,
and severe flares on the Safety of Estrogens in
Lupus Erythematosus National Assessment (SELENA)-
SLEDAI Flare Index (SSFI); and proportion of patients
achieving Lupus Low Disease Activity Score (LLDAS).
We also recorded corticosteroid doses and measured
changes in serological markers, including anti-dsDNA
and complement component (C) 3 and C4. We assessed
change in the patient-reported outcomes Worst Joint
Pain numeric rating scale (NRS), Worst Pain NRS, and
Worst Fatigue NRS (appendix pp 20–23).
Incidence and severity of all adverse events were
recorded between baseline and week 24, and up to
30 days after treatment had ended, and the Quick
Inventory of Depressive Symptomatology Self-Rated-16
was assessed. We used the National Institutes of
Health Common Terminology Criteria for Adverse
Events (CTCAE) to describe laboratory abnormalities
(version 4.03).

314 randomly assigned
105 assigned to placebo 105 assigned to baricitinib 2 mg
22 discontinued
4 adverse event
5 withdrew
2 physician’s decision
9 lack of efficacy
2 other
83 completed double-blind 86 completed double-blind
treatment period
Figure 1: Trial profile
100 excluded
Statistical analysis
81 screening failure With approximately 100 patients per treatment group,
11 withdrew this study had approximately 81% power to detect a
4 physician’s decision
4 other difference of 20% between baricitinib 2 mg or 4 mg
and placebo for the primary endpoint. The expected
treatment difference was based on an expected overall
placebo response rate of 40% and an expected response
rate of 60% with baricitinib 2 mg or 4 mg. We calculated
the power for planned sample size with a two-group
104 assigned to baricitinib 4 mg χ² test of equal proportions, using nQuery Advisor
(version 7.0).
19 discontinued 18 discontinued
We analysed the primary, secondary, and exploratory
10 adverse event 11 adverse event endpoints according to the prespecified statistical
3 withdrew 1 protocol violation analysis plan.
3 physician’s 4 withdrew
decision 2 physician’s We made no multiplicity adjustments. We analysed
3 lack of efficacy decision efficacy and patient-reported outcomes (PGA, Worst
Pain NRS, Worst Joint Pain NRS, Worst Fatigue NRS) in
86 completed double-blind the modified intention-to-treat population, defined as all
treatment period treatment period randomly assigned patients treated with at least one
dose of study drug. We made treatment comparisons of
categorical efficacy endpoints using logistic regression,

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with treatment, region, baseline disease severity

Placebo Baricitinib Baricitinib
(SLEDAI-2K score <10 vs ≥10), and baseline anti-dsDNA (n=105) 2 mg 4 mg
status (positive or negative) in the model. We made (n=105) (n=104)
treatment comparisons of continuous efficacy endpoints Mean age, years 44·9 (12·8) 43·2 (11·0) 45·0 (12·4)
using pairwise comparisons in mixed models repeated Mean time since onset of 9·7 (7·7) 11·8 (9·1) 11·5 (10·3)
measures for outcomes with multiple post-baseline systemic lupus
values, or ANCOVA for outcomes with a single post- erythematosus, years
baseline value. The mixed models repeated measures Concomitant medications
model included treatment, baseline score, baseline Corticosteroids 77 (73%) 79 (75%) 74 (71%)
disease severity (SLEDAI-2K score <10 vs ≥10), baseline Mean prednisone dose 7·9 (4·6) 8·7 (5·8) 10·5 (17·4)
anti-dsDNA status (positive or negative), region, visit, (or equivalent), mg/day

and the interaction of treatment-by-visit as fixed Prednisone dose 36/77 (47%) 40/79 (51%) 41/74 (55%)
(or equivalent),
factors. The ANCOVA model included treatment, ≥7·5 mg/day
baseline score, baseline disease severity (SLEDAI-2K Antimalarials 75 (71%) 71 (68%) 76 (73%)
score <10 vs ≥10), baseline anti-dsDNA status (positive Immunosuppressants 45 (43%) 47 (45%) 50 (48%)
or negative), and region as explanatory variables. We Methotrexate 13 (12%) 17 (16%) 13 (13%)
made treatment comparisons for the time to first Azathioprine 15 (14%) 10 (10%) 11 (11%)
systemic lupus erythematosus flare (SSFI) using a Cox
Mycophenolate mofetil 11 (10%) 10 (10%) 16 (15%)
proportional hazards model with treatment group,
Non-steroidal 27 (26%) 29 (28%) 32 (31%)
baseline disease severity (SLEDAI-2K score <10 vs ≥10), anti-inflammatory drug
baseline anti-dsDNA status (positive or negative), and Mean SLEDAI-2K score* 8·9 (2·9) 8·8 (3·4) 9·0 (3·3)
region fitted as explanatory variables. We assessed safety SLEDAI-2K score ≥10 43 (41%) 35 (33%) 44 (42%)
in patients who received at least one dose of study SLEDAI-2K organ system involvement
drug and who were not lost to follow-up before the CNS 3 (3%) 1 (1%) 2 (2%)
first post-baseline visit. Adverse events were inclusive Vascular 1 (1%) 4 (4%) 3 (3%)
of the treatment period and up to 30 days after treat­ Musculoskeletal 93 (89%) 93 (89%) 96 (92%)
ment, and laboratory abnormality summaries included Renal 9 (9%) 9 (9%) 7 (7%)
the treatment period and up 60 days after treatment.
Mucocutaneous 90 (86%) 82 (78%) 92 (88%)
We used the Fisher exact test for all adverse events,
Cardiovascular and 2 (2%) 1 (1%) 1 (1%)
discontinuation, and other categorical safety data. We respiratory
analysed continuous safety data using ANCOVA, Immunological 62 (59%) 63 (60%) 64 (62%)
adjusting for baseline value and treatment. All analyses Constitutional 2 (2%) 2 (2%) 0
were assessed at a two-sided α of 0·05. Haematological 13 (12%) 9 (9%) 5 (5%)
For categorical efficacy analyses, patients were con­ ≥1 A or ≥2 B BILAG scores† 62 (59%) 56 (53%) 69 (66%)
sidered non-responders at each visit if they were not Mean Physician’s Global 49·5 (16·9) 48·8 (15·8) 51·7 (16·0)
responders at that visit; permanently discontinued study Assessment score‡
treatment at any time before that visit for any reason; Mean CLASI activity score§ 4·9 (5·7) 3·8 (5·4) 4·0 (3·4)
required initiation or increase (from baseline) in dose Mean tender joint count 7·7 (5·8) 8·7 (6·6) 8·5 (6·2)
of non-steroidal anti-inflamma­ tory drugs (for 30 or Mean swollen joint count 5·3 (4·7) 5·2 (4·7) 5·5 (4·2)
more consecutive days), cortico­steroids, antimalarials, Mean SLICC/ACR Damage 0·59 (0·97) 0·44 (0·68) 0·40 (0·88)
or immunosuppressants, after randomisation; or had Index score¶
missing data at that visit. No imputation was needed Data are mean (SD), n (%), or n/N (%). Additional baseline characteristics and
with mixed models repeated measures for analysing the disease activity are described in the appendix (pp 24–25). SLEDAI-2K=Systemic
continuous efficacy endpoints. This study is registered Lupus Erythematosus Disease Activity Index-2000. BILAG=British Isles Lupus
Assessment Group. CLASI=Cutaneous Lupus Erythematosus Disease Area and
with ClincialTrials.gov, number NCT02708095. Severity Index. SLICC=Systemic Lupus International Collaborating Clinics.
ACR=American College of Rheumatology. *Scores range from 0 to 105, with
Role of the funding source higher values indicating more severe disease. †A score indicates severe disease
and B score indicates moderate disease. ‡Scores range from 0 (0 mm) to
The funder of the study had a role in study design, data
3 (100 mm; visual analogue scale), with higher values indicating more severe
analysis, data collection, data interpretation, or writing of disease. §Scores range from 0 to 70, with higher values indicating greater
the report. The corresponding author had full access to severity. ¶Scores range from 0 to 45, with higher values indicating
all the data in the study and had final responsibility for more damage.

the decision to submit for publication. Table 1: Baseline characteristics and disease activity

Results
Between March 24, 2016, and April 27, 2017, 314 patients (n=104); 255 (81%) completed the 24-week double-blind
were randomly assigned to receive once-daily placebo treatment period (figure 1). No patients were excluded
(n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg from the efficacy and safety analyses.

www.thelancet.com Vol 392 July 21, 2018 225

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A Resolution of arthritis or rash (SLEDAI-2K) B SRI-4 response

100 Placebo 100
Baricitinib 2 mg
Baricitinib 4 mg
80 80
Patients (%)

60 60

40 40

20 20

0 0
0 2 4 8 12 16 20 24 0 2 4 8 12 16 20 24
p value
Baricitinib 2 mg 0·97 0·57 0·54 0·91 0·15 0·38 0·39 0·72 0·34 0·42 0·67 0·25 0·48 0·44
Baricitinib 4 mg 0·56 0·18 0·56 0·26 0·06 0·0293 0·0414 0·55 0·12 0·48 0·33 0·34 0·09 0·0151

C SLEDAI-2K score D Physician’s Global Assessment

0 0
Least squares mean change from

–1·0
–10

–2·0
baseline

–20
–3·0

–30
–4·0

–5·0 –40
0 2 4 8 12 16 20 24 0 2 4 8 12 16 20 24
Time (weeks) Time (weeks)
p value
Baricitinib 2 mg 0·77 0·72 0·68 0·98 0·28 0·97 0·60 0·38 0·98 0·60 0·31 0·11 0·37 0·87
Baricitinib 4 mg 0·31 0·66 0·98 0·88 0·30 0·42 0·24 0·41 0·34 0·26 0·08 0·41 0·08 0·0218

Figure 2: Primary and secondary efficacy analyses

(A) Proportion of patients achieving resolution of arthritis or rash, as determined by SLEDAI-2K. (B) Proportion of patients achieving an SRI-4 response.
(C) Least squares mean change from baseline in the SLEDAI-2K score (scores ranging from 0 to 105, higher scores indicate more severe disease). (D) Least
squares mean change from baseline in the Physician’s Global Assessment of Disease Activity, with scores ranging from 0 (0 mm) to 3 (100 mm; visual analogue
scale, higher scores indicate more severe disease). The figure includes all patients in the modified intention-to-treat analysis (n=314). p values are for
comparisons of baricitinib 2 mg and 4 mg with placebo. SLEDAI-2K=Systemic Lupus Erythematosus Disease Activity Index-2000. SRI-4=Systemic Lupus
Erythematosus Responder Index-4.

Baseline demographics and disease activity were improvement in the primary outcome measure for the
similar among groups (table 1; appendix). 294 (94%) baricitinib 2 mg group (61 [58%] of 105 patients;
patients were female and the mean age at baseline was OR 1·3, 95% CI 0·7–2·3; p=0·39), but this was not
44 years (SD 12). At baseline, the mean duration of statistically significant. The proportion of patients
systemic lupus erythematosus was 11 years (SD 9), with achieving an SRI-4 response at week 24 was higher in
a mean SLICC/ACR index of 0·5 (SD 0·9). Patients the baricitinib 4 mg group than in the placebo group
had a baseline mean SLEDAI-2K score of 8·9 (SD 3), (67 [64%] patients; OR 2·0, 95% CI 1·2–3·6; p=0·0151);
mean tender joint count of 8·3 (SD 6), and mean the result did not reach significance for baricitinib
swollen joint count of 5·3 (SD 5). Patients had a mean 2 mg (54 [51%] patients; OR 1·3, 95% CI 0·7–2·2;
baseline CLASI index score of 4·2 (SD 5). 187 (60%) p=0·44; figure 2, table 2). The achievement of SRI-4 at
patients had worsening of disease, as indicated by week 24 was primarily driven by the SLEDAI-2K
BILAG score criteria. At baseline, 230 (73%) patients component (67 [64%] patients in the baricitinib 4 mg
were receiving corticosteroids, 222 (71%) were receiving group, OR vs placebo 2·0, 95% CI 1·1–3·5, p=0·0220;
antimalarials, and 142 (45%) were receiving immuno­ 55 [52%] patients in the baricitinib 2 mg group, 1·2,
suppressants. 0·7–2·2, p=0·45; table 2). For the other secondary
The proportion of patients who achieved resolution endpoints, there was a significant decrease in PGA at
of arthritis or rash (SLEDAI-2K), the primary outcome, week 24 for patients who received baricitinib 4 mg
was significantly higher in the baricitinib 4 mg group versus placebo; results were not significant for the
than in the placebo group (70 [67%] of 104 patients; baricitinib 2 mg group (table 2, figure 2). Pharma­
odds ratio [OR] vs placebo 1·8, 95% CI 1·0–3·3; cokinetic and pharma­codynamic models showed that
p=0·0414; figure 2A, table 2). There was also the majority of patients in the baricitinib 4 mg

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Placebo Baricitinib 2 mg (n=105) Baricitinib 4 mg (n=104)

(n=105)
Week 24 Week 24 Comparison with placebo Week 24 Comparison with placebo
(95% CI); p value (95% CI); p value
Primary outcome
Resolution of arthritis/rash (SLEDAI-2K)* 56 (53%) 61 (58%) 1·3 (0·7 to 2·3); p=0·39 70 (67%) 1·8 (1·0 to 3·3); p=0·0414
Secondary and exploratory outcomes
SRI-4* 50 (48%) 54 (51%) 1·3 (0·7 to 2·2); p=0·44 67 (64%) 2·0 (1·2 to 3·6); p=0·0151
≥4 point improvement in SLEDAI-2K* 51 (49%) 55 (52%) 1·2 (0·7 to 2·2); p=0·45 67 (64%) 2·0 (1·1 to 3·5); p=0·0220
No worsening (≥1A/2B) by BILAG* 80 (76%) 82 (78%) 1·2 (0·6 to 2·2); p=0·67 85 (82%) 1·4 (0·7 to 2·8); p=0·31
No worsening by PGA* 78 (74%) 82 (78%) 1·3 (0·7 to 2·5); p=0·45 84 (81%) 1·5 (0·8 to 2·9); p=0·26
LLDAS* 27 (26%) 35 (33%) 1·4 (0·8 to 2·7); p=0·25 40 (38%) 1·9 (1·0 to 3·5); p=0·0391
Flares (any severity) on the 54 (51%) 45 (43%) 1·0 (0·6 to 1·5); p=0·88 34 (33%) 0·6 (0·4 to 0·9); p=0·0193
SELENA-SLEDAI Flare Index†
Severe flares on the SELENA-SLEDAI 12 (11%) 10 (10%) 1·0 (0·4 to 2·3); p=0·98 6 (6%) 0·5 (0·2 to 1·3); p=0·17
Flare Index†
Least squares mean change from baseline‡
SLEDAI-2K –3·8 (0·4) –4·1 (0·4) –0·3 (–1·2 to 0·7); p=0·60 –4·4 (0·4) –0·6 (–1·6 to 0·4); p=0·24
PGA –26·3 (1·8) –25·9 (1·8) 0·4 (–4·6 to 5·4); p=0·87 –32·2 (1·8) –5·9 (–10·9 to –0·9); p=0·0218
CLASI activity score –2·8 (0·4) –1·7 (0·4) 1·1 (0·1 to 2·2); p=0·0371 –2·3 (0·4) 0·5 (–0·5 to 1·6); p=0·33
28-tender joint count –5·6 (0·4) –6·5 (0·4) –0·9 (–2·1 to 0·3); p=0·13 –6·9 (0·4) –1·3 (–2·5 to –0·1); p=0·0377
28-swollen joint count –4·6 (0·2) –4·1 (0·2) 0·5 (–0·2 to 1·1); p=0·14 –4·8 (0·2) –0·2 (–0·8 to 0·5); p=0·60
SLICC/ACR Damage Index score 0·05 (0·03) 0·07 (0·03) 0·03 (–0·05 to 0·10); p=0·53 0·07 (0·03) 0·03 (–0·05 to 0·10); p=0·52
Worst Joint Pain NRS –0·9 (0·3) –1·6 (0·3) –0·6 (1·3 to 0·1); p=0·07 –1·8 (0·3) –0·9 (–1·6 to –0·2); p=0·0157
Worst Pain NRS –0·6 (0·3) –1·2 (0·3) –0·6 (–1·3 to 0·1); p=0·10 –1·3 (0·3) –0·8 (–1·5 to 0); p=0·0403
Worst Fatigue NRS –1·2 (0·2) –1·1 (0·2) 0·1 (–0·6 to 0·7); p=0·89 –1·5 (0·2) –0·3 (–1·0 to 0·3); p=0·32
Anti-dsDNA, IU/mL 55·4 (26·8) 1·0 (27·1) –54·4 (–128·0 to 19·2); p=0·15 48·5 (26·9) –6·8 (–80·6 to 66·9); p=0·86
Complement C3, g/L 0 (0·02) 0 (0·02) –0·01 (–0·06 to 0·04); p=0·75 –0·02 (0·02) –0·02 (–0·07 to 0·02); p=0·31
Complement C4, g/L 0·01 (0·01) –0·01 (0·01) –0·01 (–0·03 to 0); p=0·18 –0·01 (0·01) –0·02 (–0·03 to 0); p=0·0314
Data are n (%) or least squares mean (SE). 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. SLEDAI-2K=Systemic Lupus
Erythematosus Disease Activity Index-2000. SRI-4=Systemic Lupus Erythematosus Responder Index-4. BILAG=British Isles Lupus Assessment Group. PGA=Physician’s
Global Assessment of Disease Activity. LLDAS=Lupus Low Disease Activity Score. SELENA=Safety of Estrogens in Lupus Erythematosus National Assessment.
CLASI=Cutaneous Lupus Erythematosus Disease Area and Severity Index. SLICC=Systemic Lupus International Collaborating Clinics. ACR=American College of
Rheumatology. NRS=Numeric Rating Scale. dsDNA=double-stranded DNA. *Comparisons are odds ratios. †Comparisons are hazard ratios for time to event.
‡Comparisons are least squares mean difference.

Table 2: Clinical and biomarker outcomes at week 24 in the intention-to-treat population

group had exposure at the plateau of the curve (data
not shown).
There were some improvements in exploratory
outcomes, including patient-reported outcomes, with
baricitinib treatment. A greater proportion of patients
attained LLDAS with baricitinib 4 mg than with placebo
at week 24 (p=0·0391); the result did not reach
significance for baricitinib 2 mg (table 2). A decreased
risk of any flare, as measured by the SSFI, was observed
for patients receiving baricitinib 4 mg compared
with placebo at week 24 (p=0·0193); the result did not
reach significance for baricitinib 2 mg (table 2,
figure 3). There were significant improvements in
28-tender joint count (p=0·0377), Worst Joint Pain NRS
(p=0·0157), and Worst Pain NRS (p=0·0403) for
patients receiving baricitinib 4 mg compared with
those receiving placebo at week 24 (table 2, figure 3;
appendix). Treatment with baricitinib 4 mg did not
result in significant improve­ments at week 24 in other
exploratory assessments. Results of the exploratory
analyses were not significant for the baricitinib 2 mg
group compared with placebo at week 24, for most
measures (table 2).
Rates of treatment discontinuation because of adverse
events are shown in table 3. Serious adverse events
were reported in five (5%) patients receiving placebo,
11 (10%) patients receiving baricitinib 2 mg, and
ten (10%) patients receiving baricitinib 4 mg (table 3,
appendix). There were no deaths, malignancies, or
major adverse cardiovascular events in the study. 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 (six [6%] patients) than in the 2 mg group

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A Tender joint count, 0–28 B Swollen joint count, 0–28

0 0
Placebo
Least squares change from baseline
–1 Baricitinib 2 mg –1
–2 Baricitinib 4 mg
–2
–3
–4 –3
–5
–4
–6
–5
–7
–8 –6
0 2 4 8 12 16 20 24 0 2 4 8 12 16 20 24
p value
Baricitinib 2 mg 0·36 0·29 0·08 0·66 0·51 0·38 0·13 0·70 0·99 0·10 0·0170 0·0054 0·0201 0·14
Baricitinib 4 mg 0·96 0·15 0·14 0·16 0·22 0·0235 0·0377 0·45 0·83 0·77 0·86 0·73 0·38 0·60

C Time to flare, any severity D Time to severe flare

0·7 Baricitinib 2 mg HR 1·0 (95% CI 0·6–1·5); p=0·88 0·25 Baricitinib 2 mg HR 1·0 (95% CI 0·4–2·3); p=0·97
Baricitinib 4 mg HR 0·6 (95% CI 0·4–0·9); p=0·019 0·612 Baricitinib 4 mg HR 0·5 (95% CI 0·2–1·3); p=0·17 0·221
0·6
0·20
0·5
Cumulative event

0·463
0·4 0·15
0·337 0·120
0·3 0·10
0·2 0·060
Placebo 0·05
0·1 Baricitinib 2 mg
Baricitinib 4 mg
0 0
0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28
Time (weeks) Time (weeks)
Number at risk
Placebo 105 78 70 65 60 52 39 0 105 96 92 90 84 81 64 0
Baricitinib 2 mg 105 77 68 63 61 59 41 0 105 96 90 89 87 83 63 0
Baricitinib 4 mg 104 86 81 76 71 67 53 0 104 100 96 93 87 85 64 0

Figure 3: Improvements in systemic lupus erythematosus disease activity, weeks 0–24

The least squares mean change from baseline in tender joint count (A) and swollen joint count (B). Time to first flare of any severity (C) and time to first severe
flare (D), as defined by the SSFI. p values are for comparisons of baricitinib 2 mg and 4 mg with placebo. HR=hazard ratio. SSFI=Safety of Estrogens in Lupus
Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index Flare Index.

(two [2%] patients) or placebo group (one [1%] patient; observed for other conditions,9–14 and four led to
table 3, appendix). There were no cases of serious discontinuation of study drug (n=2 in baricitinib 2 mg
or multi­dermatomal herpes zoster virus infection or and n=2 in baricitinib 4 mg).
opportunistic infection, and no reports of tuberculosis.
There was one occurrence of non-serious herpes zoster Discussion
virus infection in the placebo group, none in the Use of 4 mg daily oral baricitinib treatment, in addition
baricitinib 2 mg group, and one in the baricitinib to standard of care therapy, was superior to placebo plus
4 mg group. standard of care in improving signs and symptoms of
Mean changes from baseline and CTCAE grade active systemic lupus erythematosus.
increases for selected laboratory analytes from baseline We chose the primary objective, resolution of arthritis
to week 24 are shown in the appendix. There were or rash by SLEDAI-2K, for this phase 2 trial because
modest dose-associated decreases in haemoglobin and arthritis and rash are among the most common
neutrophil concentrations. There were early increases manifestations of systemic lupus erythematosus and are
in lymphocyte concentration with baricitinib treatment, the two most frequent clinical manifestations at entry
but lymphocytes returned to baseline concentrations by in recent clinical trials of extra-renal systemic lupus
week 24. At week 12, there were statistically significant erythematosus. The SLEDAI-2K organ domain scoring
dose-associated increases in platelet counts, creatine is a validated, widely used outcome measure for the
phosphokinase, HDL cholesterol, and total cholesterol study of systemic lupus erythematosus.15,16 Arthritis, as
(appendix). There were modest dose-associated inc­ well as musculoskeletal pain, is a prominent symptom
reases in triglyceride concentrations in the baricitinib in patients with systemic lupus erythematosus, and
groups. There were no clinically meaningful differences improvement in musculoskeletal symptoms, assessed
in laboratory abnormalities. Laboratory changes were with several measures, is associated with improvement in
generally of low grade and consistent with changes quality of life.17–20 Treatment with 4 mg baricitinib showed,

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by physician assessment, improve­ment in the proportion

Placebo Baricitinib Baricitinib
of patients with arthritis, as measured using the (n=105) 2 mg (n=105) 4 mg (n=104)
SLEDAI-2K arthritis organ domain score (data not
Discontinuation from 4 (4%) 10 (10%) 11 (11%)
shown), and improvement in the proportion with joint study treatment because
tenderness, as measured by 28-joint examination. of an adverse event
Treatment with 4 mg baricitinib also showed a significant Any adverse event after 68 (65%) 75 (71%) 76 (73%)
reduction in the proportion of patients with Worst Joint the start of therapy
Pain and Worst Pain when compared with placebo. Infections 41 (39%) 47 (45%) 47 (45%)
In this phase 2 study, it was also important to bench­mark Serious infections 1 (1%) 2 (2%) 6 (6%)
improvement with an established composite endpoint, Herpes zoster virus 1 (1%) 0 1 (1%)
SRI-4, which assesses overall disease activity improvement infection

with a global disease index. SRI-4 is a validated, widely Deep-vein thrombosis 0 0 1 (1%)
accepted clinical trial and global regulatory endpoint for Serious adverse events 5 (5%) 11 (10%) 10 (10%)
studies of systemic lupus erythematosus.21 Additional Data are n (%). Adverse events that occurred between baseline and week 24, and
results supporting the findings for the primary endpoint up to 30 days after treatment, are shown.

were the significant improvements in SRI-4 for patients
in the baricitinib 4 mg group, as well as other important
general measures of disease activity, such as PGA,
LLDAS, SSFI flares, and patient-reported outcomes.
Baricitinib 2 mg did not show any significant differences
from placebo across the primary and secondary efficacy
objectives studied at week 24, although there were
improvements compared with placebo.
There were no significant improvements in the signs
or symptoms of skin disease, whether measured using
proportions of patients meeting the SLEDAI-2K muco­
cutaneous organ domain score (data not shown) or using
the CLASI activity score for severity, when comparing
placebo with baricitinib 2 mg or 4 mg. Although the
percentage of patients at baseline with mucocutaneous
disease activity, measured by SLEDAI-2K, was high
(84%), the overall activity score for severity, as measured
by CLASI, was low. Currently, there are limited data
about the use of CLASI in phase 2 or 3 clinical trials in
systemic lupus erythematosus; hence, the use of CLASI
remains uncertain. A mean baseline CLASI activity score
of 4·2, as seen in this study, might be inadequate to
discern a difference between placebo and treatment with
baricitinib 2 mg or 4 mg, 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 dermatological conditions including
atopic dermatitis, psoriasis, graft-versus-host disease,
and alopecia areata, and there remains reason to
anticipate JAK inhibitors could have potential efficacy in
treating the mucocutaneous features of systemic lupus
erythematosus.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 with
results from studies of baricitinib for other
conditions.9–14 Compared with placebo, baricitinib
treatment was associated with a higher proportion of
patients who discontinued study treatment because of
adverse events, and serious adverse events were more
Table 3: Adverse events
frequent with baricitinib treatment. However in this
study, serious infection rates were more frequent with
baricitinib 4 mg (6%) than with baricitinib 2 mg (2%) or
placebo (1%). The serious infection rate 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 might be
affected by the frequent use 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.
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 this study,
which occurred in a patient receiving baricitinib 4 mg,
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 (data not
shown). No patients were excluded from the study based
on risk factors, including history of thrombosis (unless
the occurrence was recent—ie, within the previous
24 weeks).
Although there were no clinically meaningful
differences in laboratory abnormalities, baricitinib
treatment resulted in modest dose-associated decreases
in haemoglobin neutrophil, and triglyceride concen­
trations, and statistically significant increases in platelet
counts, concentrations of creatine phosphokinase, HDL
cholesterol, and total cholesterol.
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 shown 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 might be
seen in a 52-week study. Patients were allowed to

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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 trials for systemic lupus
erythematosus,26 but despite this confounder, the results
were positive.
Despite treatment advances, systemic lupus erythema­
tosus remains a disease with unacceptable morbidity
and mortality.27 Existing treatments can be associated
with incomplete efficacy or substantial toxicity.28 Since
baricitinib has selectivity for JAK1 and JAK2,5 it could
inhibit pathways that have been implicated as central to
the pathogenesis of systemic lupus erythematosus, and
we hypothesised that baricitinib could have clinical
benefit in active systemic lupus erythematosus. We
found that once-daily baricitinib 4 mg was associated
with significant clinical improvements compared with
placebo. Baricitinib treatment was not associated with
any notable safety findings compared with 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.
Contributors
All authors contributed to the concept and design of the study, data
analysis and interpretation, critical revision of the publication, and final
approval to submit, and were accountable for the accuracy and integrity of
the publication.
Declaration of interests
DJW has received consulting support from Amgen, Eli Lilly and
Company, EMD Merck Serono, and Pfizer. RAF has received
consulting support from Eli Lilly and Company. YT has received grant
support, 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. KCK has received consulting support
from Eli Lilly and Company. MM has received consulting support from
Eli Lilly and Company. MAP has received consulting support from
Eli Lilly and Company. TD has received grant support, 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. MHC has received grant
support, research support, consulting support, or speaker bureau fees
from AbbVie, Eli Lilly and Company, Gilead, Janssen, Pfizer, and
Roche. INB has received grant support, research support, consulting
support, or speaker bureau fees from AstraZeneca, BMS, Eli Lilly and
Company, Genzyme, GlaxoSmithKline, Merck Serono, and UCB. EG,
AMD, JMJ, MDL, SdB, MES, and RWH are employees and
stockholders of Eli Lilly and Company. TC is an employee of Eli Lilly
and Company.
Acknowledgments
We would like to thank the patients who participated in the study,
Nicole Byers (Eli Lilly and Company) for assisting with manuscript
preparation and process support, and Julie Sherman (Eli Lilly and
Company) for figure assistance. Eli Lilly or its representatives provided
data, laboratory, and site monitoring services. INB 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 National Health Service, the NIHR, or the
Department of Health.
230 www.thelancet.com Vol 392 July 21, 2018
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