Articles

Guselkumab in patients with active psoriatic arthritis who

were biologic-naive or had previously received TNFα
inhibitor treatment (DISCOVER-1): a double-blind,
randomised, placebo-controlled phase 3 trial
Atul Deodhar, Philip S Helliwell, Wolf-Henning Boehncke, Alexa P Kollmeier, Elizabeth C Hsia, Ramanand A Subramanian, Xie L Xu,
Shihong Sheng, Prasheen Agarwal, Bei Zhou, Yanli Zhuang, Christopher T Ritchlin, on behalf of the DISCOVER-1 Study Group

Summary
Background Many patients with psoriatic arthritis have an inadequate response to tumour necrosis factor (TNF) Lancet 2020; 395: 1115–25
inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly Published Online
improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. March 13, 2020
https://doi.org/10.1016/
S0140-6736(20)30265-8
Methods This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in
This online publication has
13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis been corrected. The corrected
(at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. version first appeared at
Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months thelancet.com on
March 20, 2020
of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks
See Comment page 1091
of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously
received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; See Articles page 1126

stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; Division of Arthritis and
Rheumatic Diseases, Oregon
guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American Health and Science University,
College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using Portland, OR, USA
non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at (Prof A Deodhar MD); Leeds
ClinicalTrials.gov, NCT03162796 (active, not recruiting). Institute of Rheumatic and
Musculoskeletal Medicine,
University of Leeds, Leeds, UK
Findings From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated (Prof P S Helliwell MD);
with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued National Institute for Health
study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater Research Leeds
Musculoskeletal Biomedical
proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50–68]) and every 8 weeks group Research Centre, Leeds, UK
(66 [52%] of 127 [43–61]) than in the placebo group (28 [22%] of 126 [15–30]), with percentage differences versus placebo (Prof P S Helliwell); Division of
of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0·0001). Serious Dermatology and Venerology,
adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving Geneva University Hospitals,
Geneva, Switzerland
guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died (Prof W-H Boehncke MD);
from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. Immunology, Janssen Research
and Development, San Diego,
Interpretation Guselkumab demonstrated a favourable benefit–risk profile and might be an effective treatment option CA, USA (A P Kollmeier MD,
X L Xu PhD); Immunology
for patients with active psoriatic arthritis. (E C Hsia MD,
R A Subramanian PhD), Clinical
Funding Janssen Research and Development. Pharmacology and
Pharmacometrics
(Y Zhuang PhD), and Clinical
Copyright © 2020 Elsevier Ltd. All rights reserved. Biostatistics (S Sheng PhD,
P Agarwal PhD, B Zhou PhD),
Introduction with a different mechanism of action can be a useful Janssen Research and
Development, Spring House,
As a heterogeneous inflammatory disorder, psoriatic strategy.3,4 Furthermore, patients often lose response over
PA, USA; University of
arthritis demands individualised and targeted treatment time, so new mechanisms to catalyse development of Pennsylvania Medical Center,
based on specific clinical manifestations, symptom alternative treatments are needed.5,6 Philadelphia, PA, USA
severity, and comorbidities. For patients with moderate-to- Biologic treatment options for psoriatic arthritis (E C Hsia); and Allergy,
Immunology,
severe disease activity, aggressive treatment with non- include tumour necrosis factor (TNF) inhibitors, an inter­
and Rheumatology, University
biologic or biologic disease-modifying antirheumatic leukin-12/23 (IL-12/23) inhibitor, and IL-17 inhibitors. of Rochester Medical Center,
drugs (DMARDs) can substantially improve joint and skin These biologics have been shown to significantly improve Rochester, NY, USA
symptoms and prevent permanent structural damage.1,2 skin and joint responses in patients when used alone or (Prof C T Ritchlin MD)

When a patient has an inadequate response to, or is with conventional DMARDs. Other biologics and targeted
intolerant of, one biologic treatment, switching to another synthetic DMARDs are available to treat psoriatic arthritis

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Correspondence to:
Prof Atul Deodhar, Division of Research in context
Arthritis and Rheumatic
Diseases, Oregon Health and Evidence before this study
Science University, Portland, We searched PubMed on Oct 14–16, 2019, with various
OR 97239, USA combinations of the following search terms: “psoriatic
deodhara@ohsu.edu
arthritis”, “biologic”, “interleukin”, “DMARD”, “TNF inhibitor”,
“treatment”, “mechanism of action”, “guidelines”, and
“psoriasis”, for original research and review articles published
in English since Jan 1, 2010, to document outcomes associated
with existing psoriatic arthritis treatments and treatment
guidelines. Psoriatic arthritis is a heterogeneous inflammatory
disorder that often requires targeted treatment. Psoriatic
arthritis patients with either inadequate response to or
inability to tolerate one biologic might benefit from switching
to another biologic with a different mechanism of action.
Guselkumab, a high-affinity, human, anti-IL-23 monoclonal
antibody specific to the IL-23 p19 subunit that is approved to
treat moderate-to-severe psoriasis, showed efficacy in patients
with active psoriatic arthritis in a phase 2 study.
Added value of this study
These results from one of two trials comprising the first phase 3
development programme for specifically inhibiting IL-23 by
but have not demonstrated inhibition of joint damage
and appear to be less effective in resolving symptoms of
skin disease.7–9
Although TNF inhibitors are frequently chosen as the
first biologic therapy for patients with psoriatic arthritis,
a substantial proportion of patients assessed in clinical
trials do not achieve meaningful American College of
Rheumatology (ACR)-defined responses. TNF inhibitors
have a complicated safety profile, particularly with regard
to infection risk,10 and anti-IL-17 therapies have warnings
about new-onset or exacerbation of inflammatory bowel
disease in addition to infection risk.11–13
Evidence from preclinical models and clinical trial
data indicate that the IL-23/T-helper 17 (Th17) cell pathway
is pivotal in the development of both the skin and
joint manifestations of psoriatic arthritis.14,15 IL-23 is a
heterodimer composed of both p19 and p40 subunits.
See Online for appendix Guselkumab (Janssen Biotech, Horsham, PA, USA) is a
novel human monoclonal antibody that binds to the p19
subunit of IL-23 with high specificity and affinity. In a
phase 2 proof-of-concept study, guselkumab 100 mg at
week 0, week 4, and then every 8 weeks showed efficacy
across all endpoints related to joint signs and symptoms,
physical function, skin disease, enthesitis, dactylitis, and
health-related quality of life.16 In biomarker assessments
from that study, guselkumab-treated patients demon­
strated decreased serum concentrations of IL-17A, IL-17F,
and C-reactive protein (CRP), with IL-17A and IL-17F levels
similar to those of healthy controls by week 16. These
changes were associated with 20% or greater improvement
in ACR response criteria (ACR20) and psoriasis area and
severity index (PASI) 75% improve­ment responses.17 Such
1116
binding the IL-23 p19 subunit in psoriatic arthritis provide
pivotal evidence of guselkumab efficacy in this indication.
Across patients with active disease, guselkumab 100 mg
significantly improved joint symptoms, physical function,
skin symptoms of psoriasis, and health-related quality of life
when administered every 4 or 8 weeks. Improvements in
disease activity were equally robust in patients who had
received or had inadequate response to one or two TNF
inhibitors. For both guselkumab dose regimens, the safety
profile up to week 24 in patients with psoriatic arthritis was
consistent with that in patients treated for psoriasis.
Implications of all the available evidence
Results of this confirmative phase 3 trial provide strong
evidence that guselkumab offers a novel mechanism of action,
via targeting the p19 subunit of IL-23, to treat the diverse
peripheral clinical manifestations of psoriatic arthritis.
Guselkumab might provide an additional treatment option for
patients with psoriatic arthritis with active disease despite
previous receipt of standard therapies, including TNF
inhibitors.
associations confirm the rele­ vance of the IL-23/Th17
pathway in psoriatic arthritis and that of guselkumab
treatment in suppressing the pathway common to both
skin and joint pathologies.
Here, we report results from one of two pivotal phase 3
trials (DISCOVER-1), conducted to assess guselkumab
in patients with active psoriatic arthritis, including
those who were previously treated with one or two TNF
inhibitors. Results from the other phase 3 registrational
trial of guselkumab in psoriatic arthritis (DISCOVER-2),
which sought to enrol biologic-naive patients with psori­
atic arthritis who had higher levels of disease activity, are
reported separately.18
Methods
Study design
DISCOVER-1 is a randomised, double-blind, placebo-
controlled, multicentre (appendix p 10), international,
three-arm phase 3 trial of guselkumab in patients with
active psoriatic arthritis despite standard therapies (non-
biologic DMARDs, apremilast, and non-steroidal anti-
inflam­matory drugs [NSAIDs]). The trial was done at
86 sites in 13 countries (Australia, Canada, Czech Republic,
Germany, Hungary, Malaysia, Poland, South Korea, Russia,
Spain, Taiwan, Ukraine, and the USA). This trial
conformed with the Declaration of Helsinki and Good
Clinical Practice guidelines. The protocol was approved by
each site’s governing ethical body.
Participants
We enrolled patients fulfilling classification criteria for
psoriatic arthritis and displaying at least three tender and
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at least three swollen joints and CRP concentration of
0·3 mg/dL or more. Eligible patients had a current or
documented history of psoriasis and had demonstrated
inadequate response to or intolerance of standard treat­
ment, including at least 4 months of apremilast (if
discontinued >4 weeks before receiving study treat­ment),
at least 3 months of non-biologic DMARDs (limited to
methotrexate ≤25 mg/week, sulfasalazine ≤3 g/day,
hydroxy­ chloroquine ≤400 mg/day, or leflunomide
≤20 mg/day), or at least 4 weeks of NSAIDs for psoriatic
arthritis. About 30% of enrolled patients could have been
previously treated with one or two TNF inhibitors.
Patients were permitted, but not required, to continue
background use of stable doses of one selected non-
biologic DMARD, oral corticosteroids (≤10 mg/day of
prednisone or equiva­lent dose), and NSAIDs or other
analgesics. Patients with other inflammatory diseases
and those who had previously received biologics other
than TNF inhibitors were excluded. Patients also had
to meet criteria for screening laboratory testing and
tuberculosis history, testing, and treatment (for latent
tuberculosis). Full inclusion and exclusion criteria are in
the appendix (pp 2–8). All patients provided written
informed consent.
Randomisation and masking
At week 0, patients were centrally randomly assigned using
an interactive web response system (with computer-
generated permuted-block randomisation stratified by
baseline non-biologic DMARD use [yes vs no] and previous
TNF inhibitor use [yes vs no]) in a 1:1:1 ratio to receive
guselkumab 100 mg every 4 weeks; guselkumab 100 mg
at week 0, week 4, and then every 8 weeks; or placebo.
Placebo and guselkumab were provided in identical
prefilled syringes with non-identifying labels, and patients
in each treatment group received the same number of
injections at the same timepoints to ensure that patients
and all study site personnel were masked to treatment
assignment throughout the study.
Procedures
Following a 6-week screening period, the study included a
placebo-controlled period from week 0 to week 24 and an
active treatment period from week 24 to week 52 (last

624* patients screened

241 did not meet inclusion criteria

135 C-reactive protein too low
33 exclusionary laboratory parameter
18 did not meet tuberculosis criteria
55 other

382 enrolled

128 randomly assigned to guselkumab 128 randomly assigned to guselkumab 126 randomly assigned to placebo
100 mg every 4 weeks 100 mg every 8 weeks

1 did not start treatment

128 started treatment 127 started treatment 126 started treatment

3 discontinued study treatment 4 discontinued study treatment 12 discontinued study treatment

1 adverse events 3 adverse events 2 adverse events
1 withdrew consent 1 other 4 inadequate efficacy
1 other 1 initiated protocol-prohibited
medication
3 withdrew consent
1 lost to follow-up
1 death

125 continuing treatment at week 24 123 continuing treatment at week 24 114 continuing treatment at week 24

Figure 1: Trial profile

One patient was accidentally randomly assigned before completion of the screening assessments. Subsequently, this patient did not pass screening and was later
rescreened and randomly assigned using a new patient number. Three patients in the every 4 weeks group, four in the every 8 weeks group, and 24 in the placebo
group were eligible for early escape at week 16. *623 unique patients.

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administration at week 48). Safety follow-up continued for early escape—ie, they continued with study treatment
for 12 weeks after the final dose of study drug (week 60). but the investigator could initiate or increase the dose of
At week 16, all patients with less than 5% improvement NSAIDs or other analgesics (up to the regional marketed
in both swollen and tender joint counts were eligible dose approved), oral corticosteroids (≤10 mg/day of pred­
nisone or equivalent dose), or non-biologic DMARDs (per
study inclusion criteria). At week 24, all placebo patients
Guselkumab 100 mg Placebo (n=126)
began to receive guselkumab 100 mg every 4 weeks up to
Every 4 weeks Every 8 weeks week 48. Herein, we report week 24 results.
(n=128) (n=127)
Guselkumab was administered as a 100-mg subcuta­
Age, years 47·4 (11·6) 48·9 (11·5) 49·0 (11·1) neous injection at week 0, week 4, and then every 4 weeks
Sex or every 8 weeks. The every 8 weeks regimen demonstrated
Female 62 (48%) 59 (46%) 65 (52%) robust efficacy and acceptable safety in the guselkumab
Male 66 (52%) 68 (54%) 61 (48%) phase 3 psoriasis19,20 and phase 2 psoriatic arthritis16
Race trials. The every 4 weeks regimen, which provides about
White 121 (95%) 116 (91%) 112 (89%) four times higher median steady-state trough concen­
Other* 7 (5%) 11 (9%) 14 (11%) trations versus dosing every 8 weeks (appendix p 10), was
Bodyweight, kg 86·7 (17·7) 86·3 (20·0) 85·2 (18·8) included to assess whether higher drug concentrations
Psoriatic arthritis duration, years 6·6 (6·3) 6·4 (5·9) 7·2 (7·6) could elicit greater clinical and radio­graphic efficacy in
Number of swollen joints, 0–66 8·6 (5·8) 10·9 (9·3) 10·1 (7·1) psoriatic arthritis. Up to week 24, patients in the every
Number of tender joints, 0–68 17·7 (13·1) 20·2 (14·5) 19·8 (14·4) 4 weeks group received guselkumab at weeks 0, 4, 8, 12,
Patient’s assessment of pain, 0–10 cm VAS 5·9 (2·0) 6·0 (2·1) 5·8 (2·2) 16, and 20; those in the every 8 weeks group received
Patient’s global assessment—arthritis, 0–10 cm VAS 6·1 (2·0) 6·5 (2·0) 6·1 (2·2) guselkumab at weeks 0, 4, 12, and 20 and placebo at
Physician’s global assessment, 0–10 cm VAS 6·2 (1·6) 6·2 (1·7) 6·3 (1·7) weeks 8 and 16; and those in the placebo group received
HAQ-DI score, 0–3 1·1 (0·6) 1·2 (0·6) 1·1 (0·6) placebo at weeks 0, 4, 8, 12, 16, and 20.
C-reactive protein, mg/dL 0·6 (0·3–1·3) 0·7 (0·4–1·9) 0·8 (0·3–1·5) Independent assessors evaluated joints for tenderness
Psoriatic body surface area, 0–100% 15·0% (18·0) 13·1% (18·0) 12·0% (16·0) (n=68) and swelling (n=66, excluding hips), enthesitis,
Investigator’s global assessment score of 3 or 4 62 (48%) 57 (45%) 43 (34%) and dactylitis. Patients reported their level of pain
PASI score, 0–72 9·5 (10·1) 8·4 (9·8) 7·7 (8·8) (0–10 cm visual analogue scale [VAS]), global disease
Patients with enthesitis 73 (57%) 72 (57%)† 77 (61%) activity (0–10 cm VAS), and physical function (health
Leeds enthesitis index score, 1–6‡ 3·0 (1·5) 2·7 (1·6) 2·8 (1·6) assessment questionnaire—disability index [HAQ-DI;
Patients with dactylitis 38 (30%) 49 (39%) 55 (44%) 0–3]). Investigators completed the global assessment of
Dactylitis score, 1–60§ 9·4 (12·5) 8·2 (10·0) 6·6 (7·4) disease activity (0–10 cm VAS), and serum CRP (mg/dL)
Short form-36 was measured.
Physical component summary, 0–100 35·9 (8·3) 34·1 (7·6) 33·8 (8·5)
The investigator’s global assessment (IGA) of psoriasis
Mental component summary, 0–100 46·5 (9·8) 47·0 (11·1) 48·7 (9·6)
and PASI were used to assess skin disease severity
Previous TNF inhibitor use 38 (30%) 41 (32%) 39 (31%)
and extent. The IGA averages induration, erythema, and
scaling scores to categorise the severity of psoriasis
One previous TNF inhibitor 33 (26%) 34 (27%) 35 (28%)
(0=cleared, 1=minimal, 2=mild, 3=moderate, and
Two previous TNF inhibitors 5 (4%) 7 (6%) 4 (3%)
4=severe). The PASI, which takes into account the body
Patients who did not respond to previous TNF 17 (13%) 15 (12%) 12 (10%)
inhibitor surface area affected by psoriasis, and also the degree of
Previous apremilast use 2 (2%) 6 (5%) 4 (3%) redness, scaling, and induration, ranges from 0 to 72. The
Drug use at baseline 36-item short-form (SF36) health survey physical compo­
DMARDs 82 (64%) 83 (65%) 82 (65%) nent summary (PCS) and mental component summary
Methotrexate 72 (56%) 68 (54%) 71 (56%)
(MCS) scores were used to assess health-related quality of
Methotrexate dose, mg/week 15·6 (4·1) 16·7 (5·4) 15·9 (4·5)
life (scores range 0–100 for each; USA popula­tion average
Oral corticosteroids for psoriatic arthritis 16 (13%) 18 (14%) 20 (16%)
score is 50). Suicidal ideation or behaviour or non-suicidal
self-injurious behaviour was assessed using electronic
Dose equivalent to prednisone, mg/day 6·4 (2·2) 6·0 (1·9) 6·4 (2·4)
Columbia suicide severity rating scale questionnaires.
NSAIDs for psoriatic arthritis 69 (54%) 71 (56%) 77 (61%)
Clinical assessments were done at screening, baseline,
Data presented are n (%), mean (SD), or median (IQR). DMARDs=disease-modifying antirheumatic drugs. HAQ-DI=health
and every 4 weeks up to week 24. Events were monitored
assessment questionnaire—disability index. NSAIDs=non-steroidal anti-inflammatory drugs. PASI=psoriasis area and
severity index. VAS=visual analogue scale. *Consists of native Hawaiian or other Pacific Islander (one in the every 8 weeks and routine haematology and chemistry assessments
group), not reported (two in the placebo group), and Asian (all remaining). †The denominator for this percentage is were done throughout the study, as were pharmacokinetic
126 because one patient in this group did not have the score measured at baseline. ‡Among patients with available Leeds and immunogenicity assessments (appendix p 8).
enthesitis index score at baseline (every 4 weeks group n=73; every 8 weeks group n=72; and placebo group n=77). §Among
patients with dactylitis score at baseline (every 4 weeks group n=38; every 8 weeks group n=49; and placebo group n=55).
Outcomes
Table 1: Summary of DISCOVER-1 baseline patient characteristics (all treated patients, per random group
The primary endpoint was the proportion of patients
assignment)
with an ACR20 response at week 24. Major secondary

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endpoints were ACR50 and ACR70 response, change To increase sample size, data for endpoints related to
from base­line in the 28-joint disease activity score with resolution of, and changes in, enthesitis and dactylitis
CRP (DAS28-CRP); IGA skin response (score of 0 or 1, among the smaller number of patients with those
and a ≥2-point improvement from baseline) in patients
with at least 3% body surface area of psoriasis and IGA Guselkumab 100 mg Placebo (n=126)
score of at least 2 (mild-to-severe psoriasis) at baseline; Every 4 weeks (n=128) Every 8 weeks (n=127)
change from baseline in HAQ-DI score; resolution of
Primary endpoint
enthesitis (in patients with enthesitis at baseline) and
ACR20 response at week 24 76 (59%) 66 (52%) 28 (22%)
dactylitis (in patients with dactylitis at baseline) and mean
Percentage difference vs placebo 37% (26 to 48) 30% (19 to 41) ··
changes from baseline in each score pooled across both
US procedure-adjusted p value <0·0001 <0·0001 ··
DISCOVER trials; changes from baseline in SF-36 PCS
Major secondary endpoints controlled by US procedure
and MCS scores, all at week 24; and ACR20 and ACR50
responses at week 16. Other selected key secondary Investigator’s global assessment 67/89 (75%) 47/82 (57%) 12/78 (15%)
response at week 24*
outcomes included clinically meaningful improvement
Percentage difference vs placebo 60% (48 to 72) 42% (29 to 55) ··
(≥0·35) in HAQ-DI score among those with baseline
US procedure-adjusted p value <0·0001 <0·0001 ··
HAQ-DI of at least 0·35; improvement in PASI scores of
HAQ-DI, least squares mean –0·40 (–0·48 to –0·31) –0·32 (–0·41 to –0·24) –0·07 (–0·16 to 0·01)
at least 75% (PASI75), 90% (PASI90), or 100% (PASI100) change at week 24
among patients with mild-to-severe psoriasis at baseline; Least squares mean difference vs –0·32 (–0·44 to –0·21) –0·24 (–0·36 to –0·13) ··
and minimal disease activity, all at week 24. Patients were placebo
considered to have achieved minimal disease activity if US procedure-adjusted p value <0·0001 <0·0001 ··
fulfilling at least five of the following seven criteria: tender Short form-36 physical 6·87 (5·60 to 8·14) 6·10 (4·83 to 7·37) 1·96 (0·69 to 3·24)
joint count 1 or less, swollen joint count 1 or less, PASI component summary, least
score 1 or less, patient pain VAS score 15 or less, patient squares mean change at week 24
global disease activity VAS score 20 or less, HAQ-DI Least squares mean difference vs 4·91 (3·19 to 6·63) 4·14 (2·42 to 5·85) ··
placebo
score 0·5 or less, and tender entheseal points 1 or less.
US procedure-adjusted p value <0·0001 <0·0001 ··
Subgroup analyses of the primary endpoint included
Major secondary endpoints not controlled by US procedure
establishing the propor­tions of patients achieving ACR20
ACR20 response at week 16 77 (60%) 66 (52%) 32 (25%)
response at week 24 by previous TNF inhibitor use and by
Percentage difference vs placebo 35% (24 to 46) 27% (15 to 38) ··
methotrexate use. A full list of endpoints is in the
Unadjusted p value <0·0001 <0·0001 ··
appendix (pp 8–10).
Safety outcomes included adverse events, serious ACR50 response at week 24 46 (36%) 38 (30%) 11 (9%)

adverse events, adverse events resulting in discontin­uation Percentage difference vs placebo 27% (18 to 37) 21% (12 to 31) ··

of study drug, infections, injection-site reactions, malig­ Unadjusted p value <0·0001 <0·0001 ··
nancies, major adverse cardiovascular events, suicidal ACR70 response at week 24 26 (20%) 15 (12%) 7 (6%)
ideation or behaviour (based on electronic Columbia Percentage difference vs placebo 15% (7 to 23) 6% (–0·3 to 13) ··
Suicide Severity Rating Scale questionnaire or reported Unadjusted p value 0·0005 0·069 ··
adverse events), and clinical laboratory abnormalities ACR50 response at week 16 34 (27%) 29 (23%) 16 (13%)
classified by National Cancer Institute common termi­ Percentage difference vs placebo 14% (4 to 23) 10% (1 to 19) ··
nology criteria for adverse events (NCI-CTCAE) grades. Unadjusted p value 0·0057 0·036 ··
A major adverse cardiovascular event was predefined as Resolution of dactylitis at week 24 24/38 (63%) 32/49 (65%) 27/55 (49%)
cardiovascular death, non-fatal myocardial infarction, Percentage difference vs placebo 13% (–7 to 34) 17% (–2 to 35) ··
or non-fatal stroke. Unadjusted p value 0·21 0·088 ··
Resolution of enthesitis at week 24 35/73 (48%) 29/72 (40%) 21/77 (27%)
Statistical analysis Percentage difference vs placebo 20% (5 to 35) 13% (–2 to 28) ··
Assuming week 24 ACR20 response rates of 40% with Unadjusted p value 0·013 0·094 ··
guselkumab versus 20% with placebo, a sample size of DAS28-CRP, least squares mean –1·61 (–1·80 to –1·42) –1·43 (–1·61 to –1·24) –0·70 (–0·89 to –0·51)
360 (120 per treatment group) would provide more than change at week 24
90% statistical power (α=0·05; two-sided) to detect a Least squares mean difference vs –0·91 (–1·16 to –0·66) –0·73 (–0·98 to –0·48) ··
placebo
treatment difference for the primary endpoint.
Treatment differences were assessed via Cochran- Unadjusted p value <0·0001 <0·0001 ··

Mantel-Haenszel testing for binary endpoints and analyses Short form-36 mental component 3·60 (2·17 to 5·02) 3·20 (1·78 to 4·63) 2·37 (0·93 to 3·81)
summary, least squares mean
of covariance for continuous endpoints. All models change at week 24
included treatment group, baseline non-biologic DMARD Least squares mean difference vs 1·23 (–0·71 to 3·16) 0·83 (–1·10 to 2·77) ··
use (yes vs no), previous TNF inhibitor use (yes vs no), and placebo
baseline value as independent variables. The 95% CIs Unadjusted p value 0·21 0·40 ··
surrounding the percentage differences versus placebo (Table 2 continues on next page)
were determined based on the Wald statistic.

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were considered non-responders for binary endpoints and

Guselkumab 100 mg Placebo (n=126)
as having no improvement from baseline for continuous
Every 4 weeks (n=128) Every 8 weeks (n=127) endpoints. Missing data were imputed as non-responders
(Continued from previous page) for binary endpoints, and multiple imputation was used
Additional secondary endpoints not controlled by US procedure to impute missing data for continuous endpoints
HAQ-DI improvement ≥0·35 at 63/110 (57%) 57/112 (51%) 32/110 (29%) assuming they were missing at random and using the
week 24† predicted value from the full conditional specification
Percentage difference vs placebo 28% (16 to 40) 22% (9 to 34) ·· regression method (requiring 200 successful imputations)
Unadjusted p value <0·0001 0·0010 ·· for any missing pattern. Each variable eligible for
PASI75 response at week 24* 77/89 (86%) 62/82 (76%) 11/78 (14%) imputation was to be restricted to only impute within its
Percentage difference vs placebo 73% (62 to 83) 62% (50 to 74) ·· possible range of values.
Unadjusted p value <0·0001 <0·0001 ·· Efficacy analyses up to week 24 included all randomly
PASI90 response at week 24* 56/89 (63%) 41/82 (50%) 9/78 (12%) assigned patients who received at least one dose of study
Percentage difference vs placebo 52% (40 to 64) 39% (26 to 51) ·· drug, analysed by assigned treatment group. Safety
Unadjusted p value <0·0001 <0·0001 ·· assessments were done in all patients who received at
PASI100 response at week 24* 40/89 (45%) 21/82 (26%) 5/78 (6%) least one dose of study drug, analysed by treatment
Percentage difference vs placebo 39% (28 to 50) 20% (10 to 30) ·· received.
Unadjusted p value <0·0001 0·0005 ·· An independent data monitoring committee examined
Minimal disease activity at week 24 39 (30%) 29 (23%) 14 (11%) data on an ongoing basis up to the week 24 database lock
Percentage difference vs placebo 19% (10 to 29) 12% (3 to 21) ·· to ensure study participant safety. Statistical analyses
Unadjusted p value 0·0002 0·012 ·· were done using SAS, version 9.4, with SAS/STAT,
version 14.2. This study is registered in Clinicaltrials.gov
Data are n (%) or n/N (%) unless otherwise specified. Ranges in parentheses are 95% CIs. One (1%) of 126 patients in the
every 4 weeks group, four (3%) of 127 in the every 8 weeks group, and eight (6%) of 128 in the placebo group met
(NCT03162796), and recruitment has finished.
treatment failure criteria. Investigator’s global assessment data were missing for one every 8 weeks patient, short form-36
physical or mental component summary scores were missing for one every 4 weeks patient, and minimal disease activity Role of the funding source
data were missing for one patient in each of the three treatment groups. Unadjusted (nominal) p values are not
controlled for multiplicity and should be interpreted only as supportive. ACR20=American College of Rheumatology
Employees of the funder had a role in study design, data
20% improvement. ACR50=ACR 50% improvement. ACR70=ACR 70% improvement. DAS28-CRP=28-joint disease collection, data analysis, data interpretation, and writing
activity score based on C-reactive protein. HAQ-DI=health assessment questionnaire—disability index. PASI75=psoriasis of the report. The corresponding author had full access
area and severity index 75% improvement. PASI90=PASI 90% improvement. PASI100=PASI 100% improvement.
to all study data and had final responsibility to submit for
*Assessed in patients with at least 3% body surface area affected by psoriasis and investigator’s global assessment score of
at least 2 at week 0. †Assessed in patients with HAQ-DI 0·35 or greater at baseline. publication.
Table 2: Summary of DISCOVER-1 efficacy findings (all treated patients, per random group assignment)
Results
We screened patients from Aug 28, 2017, to Aug 17, 2018;
conditions at baseline were prespecified to be pooled the final week 24 visit was on March 14, 2019. Among
with those from DISCOVER-2. Pooled data are reported the 624 patients screened, 241 did not meet the study
in that companion manuscript.18 entrance criteria, most commonly because CRP was less
Because of differing regional health authority require­ than 0·3 mg/dL (figure 1). 382 patients were randomly
ments for the multiplicity control of endpoints, two assigned to either the every 4 weeks group (n=128), the
prespecified statistical testing procedures were used. For every 8 weeks group (n=128), or the placebo group
both approaches, the primary endpoint was first tested (n=126). All patients received treatment except one in
for the every 4 weeks group and then for the every the every 8 weeks group, who was therefore not included
8 weeks group (each at the 0·05 level). The first approach in analyses. Three (2%) patients in the every 4 weeks
controlled the overall type 1 error rate across both dose group, four (3%) in the every 8 weeks group, and
regimens at the 0·05 level with a graphical procedure. 24 (19%) in the placebo group had less than 5% improve­
The second approach controlled the overall type 1 error ment in both tender and swollen joint counts and were
rate by each dose at the 0·05 level with a different eligible to initiate or increase the dose of NSAIDs, oral
graphical procedure (appendix p 13). Results for the corticosteroids, or per­mitted non-biologic DMARDs at
first approach are presented herein and those from the week 16. Up to week 24, more patients in the placebo
second approach are provided in the appendix (pp 10–12). than in the guselkumab groups discontinued study
Note that unadjusted (nominal) p values reported for treat­
ment, most commonly because of inadequate
endpoints not controlled for multiplicity should be efficacy. 362 (95%) of 381 patients continued the study
interpreted only as supportive. drug at week 24 (figure 1).
Data handling rules were applied to all efficacy analyses. Baseline characteristics were generally similar across
Patients who met treatment failure criteria (discontinued the groups, although a few numerical imbalances were
study treatment, terminated study participation, initiated observed (table 1). Baseline medication use was con­
or increased DMARD or oral corticosteroid use, or sistent across treatment groups; among the 381 treated
initiated protocol-prohibited psoriatic arthritis treatment) patients, 247 (65%) were receiving non-biologic DMARDs,

1120 www.thelancet.com Vol 395 April 4, 2020

 Articles

including 211 (55%) receiving methotrexate; 54 (14%)

Guselkumab 100 mg Placebo (n=126)
were receiving oral corticosteroids; and 217 (57%) were
receiving NSAIDs for psoriatic arthritis. 118 (31%) of Every 4 weeks Every 8 weeks
(n=128) (n=127)
381 patients had previously received one (102 [27%]) or
two (16 [4%]) TNF inhibitors; 44 (12%) patients had ACR20 response at week 24
discontinued TNF inhibitors use because of inadequate Patients with previous TNF inhibitor use 22/38 (58%) 23/41 (56%) 7/39 (18%)
response (table 1). Percentage difference vs placebo 40% (21 to 59) 39% (19 to 58) ··
A similar number of major protocol deviations Unadjusted p value 0·0003 0·0004 ··
occurred in the combined guselkumab groups (28 [11%] Patients with inadequate response to 11/17 (65%) 9/15 (60%) 3/12 (25%)
previous TNF inhibitor
of 255) and the placebo group (16 [13%] of 126). Five
Percentage difference vs placebo 42% (11 to 74) 36% (1 to 71) ··
patients (four guselkumab group and one placebo group)
entered the study without satisfying all eligibility criteria Patients without previous TNF inhibitor use 54/90 (60%) 43/86 (50%) 21/87 (24%)

and one patient (placebo group) received the incorrect Percentage difference vs placebo 36% (22 to 49) 26% (12 to 40) ··

treatment or dose. No deviation was considered to affect Unadjusted p value <0·0001 0·0005 ··
the overall results. ACR50 response at week 24
The study met its primary endpoint: significantly Patients with previous TNF inhibitor use 13/38 (34%) 11/41 (27%) 2/39 (5%)
greater proportions of patients achieved an ACR20 Percentage difference vs placebo 29% (13 to 45) 22% (7 to 37) ··
response at week 24 in the guselkumab every 4 weeks Unadjusted p value 0·0015 0·0078 ··
group (76 [59%] of 128 [95% CI 50–68]) and guselkumab Patients with inadequate response to 5/17 (29%) 2/15 (13%) 0/12
previous TNF inhibitor
every 8 weeks group (66 [52%] of 127 [43–61]) than in the
Percentage difference vs placebo NA NA ··
placebo group (28 [22%] of 126 [15–30]), with percentage
differences versus placebo of 37% (95% CI 26–48; Patients without previous TNF inhibitor use 33/90 (37%) 27/86 (31%) 9/87 (10%)

p<0·0001) for the every 4 weeks group and 30% (19–41; Percentage difference vs placebo 26% (14 to 38) 21% (9 to 33) ··
p<0·0001) for the every 8 weeks group (table 2). In Unadjusted p value <0·0001 0·0007 ··
prespecified subgroup analyses, consistent treatment ACR70 response at week 24
bene­fits were observed for ACR20 response at week 24 Patients with previous TNF inhibitor use 8/38 (21%) 1/41 (2%) 1/39 (3%)
with both guselkumab regimens across patient sub­ Percentage difference vs placebo 18% (5 to 32) –0% (–6 to 6) ··
groups defined by demography (eg, sex, race, and weight), Unadjusted p value 0·014* 1·0* ··
baseline disease characteristics (eg, duration of psoriatic Patients with inadequate response to 3/17 (18%) 1/15 (7%) 0/12
previous TNF inhibitor
arthritis and number of swollen or tender joints at
baseline), and previous or baseline medication use (eg, Percentage difference vs placebo NA NA ··

previous TNF inhibitor use and use of medications for
psoriatic arthritis at baseline). In particular, ACR20
response patterns at week 24 were consistent in patients
with methotrexate use at baseline (every 4 weeks:
45 [62%] of 72, every 8 weeks: 35 [52%] of 68), and in
patients with and without previous TNF inhibitor use for
both the every 4 weeks (22 [58%] of 38 with and 54 [60%]
of 90 without) and every 8 weeks (23 [56%] of 41 with and
43 [50%] of 86 without) regimens, including patients who
previously had an inadequate response to TNF inhibitors
(11 [65%] of 17 patients in the every 4 weeks group and
nine [60%] of 15 in the every 8 weeks group; table 3).
ACR20 response rates were greater in both guselkumab
groups than in the placebo group by week 8 (figure 2A).
Rates of ACR20 response at week 16 and ACR50 response
at week 24 achieved with both guselkumab dosing
regimens were higher than those associated with placebo
(table 2, figures 2A, B). The ACR70 response rate at
week 24 was significantly greater in the every 4 weeks
group than in the placebo group, but the rate in the every
8 weeks group was similar to that in the placebo group
(figure 2C). Improvements in DAS28-CRP at week 24 in
the guselkumab every 4 weeks group (least squares mean
change –1·61 [95% CI –1·80 to –1·42]) and every 8 weeks
group (–1·43 [–1·61 to –1·24]) were larger than with
placebo (–0·70 [–0·89 to –0·51]; table 2).
Patients without previous TNF inhibitor use 18/90 (20%) 14/86 (16%) 6/87 (7%)
Percentage difference vs placebo 13% (4 to 23) 9% (0 to 19) ··
Unadjusted p value 0·011 0·055 ··
Data are n/N (%) unless otherwise specified. Ranges in parentheses are 95% CIs. Unadjusted (nominal) p values are not
controlled for multiplicity and should be interpreted only as supportive. ACR20=American College of Rheumatology
20% improvement. ACR50=ACR 50% improvement. ACR70=ACR 70% improvement. NA=not applicable. TNF=tumour
necrosis factor. *Comparison vs placebo used Fisher’s exact test because of not meeting the Mantel Fleiss criterion for
Cochran-Mantel-Haenszel testing.
Table 3: Summary of DISCOVER-1 ACR response by previous TNF inhibitor use (all treated patients,
per random group assignment)
Guselkumab significantly improved skin disease as
assessed by IGA response at week 24 versus placebo
(67 [75%] of 89 patients in the every 4 weeks group and
47 [57%] of 82 in the every 8 weeks group vs 12 [15%] of
78; both p<0·0001; table 2, figure 2D). Higher PASI75,
PASI90, and PASI100 response rates were also observed
in the guselkumab groups than in the placebo group
(table 2).
Guselkumab every 4 weeks and every 8 weeks signifi­
cantly improved physical function as assessed by change
from baseline in the HAQ-DI score at week 24 (least
squares mean –0·40 [95% CI –0·48 to –0·31] in the every
4 weeks group and –0·32 [–0·41 to –0·24] in the every
8 weeks group vs –0·07 [–0·16 to –0·01] in the placebo
group; both p<0·0001; table 2, figure 2E). Further, in

www.thelancet.com Vol 395 April 4, 2020 1121

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A B Guselkumab 100 mg Placebo

100 Placebo 100 (n=126)
Guselkumab 100 mg every 8 weeks
Guselkumab 100 mg every 4 weeks Every Every
80 80
ACR20 responders (%)

ACR50 responders (%)

4 weeks 8 weeks
‡ ‡ § (n=128) (n=127)
60 ‡ 60
‡ ‡ † Length of follow-up, weeks 23·9 (0·9) 23·9 (0·8) 23·7 (2·4)
§ ‡ ‡
40 † 40
† † Number of administrations 5·9 (0·4) 5·9 (0·5) 5·8 (0·8)
† †
20 20 † ‡ Patients with one or more adverse 71 (55%) 68 (54%) 75 (60%)
* *
event
0 0 Adverse events occurring in at least 5% of patients in any group
0 4 8 12 16 20 24 0 4 8 12 16 20 24 (alphabetical order)
Week Week
Alanine aminotransferase 5 (4%) 8 (6%) 3 (2%)
increased
C D
100 100
Aspartate aminotransferase 3 (2%) 9 (7%) 3 (2%)
increased
§
80 80 ‡ 75% Nasopharyngitis 7 (5%) 16 (13%) 8 (6%)
‡
ACR70 responders (%)

IGA responders (%)

62% 64% §
57%
Upper respiratory tract infection 11 (9%) 7 (6%) 8 (6%)
60 60
Patient death 0 0 1 (1%)
40 40 Patients with one or more serious 0 4 (3%)* 5 (4%)†
‡ adverse event
20 * 20 17% 15%
Patients with adverse event 1 (1%)‡ 3 (2%)§ 3 (2%)¶
resulting in study drug
0 0 discontinuation
0 4 8 12 16 20 24 Week 16 Week 24
Week Patients with major adverse 0 0 1 (1%)
cardiovascular event
E F Patients with malignancy 0 1 (1%) 0
0 10 Patients with infection|| 31 (24%) 33 (26%) 32 (25%)
Least squares mean change from

Least squares mean change from

§ Serious infection 0 0 2 (2%)

baseline in SF-36 PCS score

–0·1 –0·07
baseline in HAQ-DI score

8 §
6·87 Patients with injection-site reaction 1 (1%) 2 (2%) 0
–0·2 6·10
6 Patients with suicidal ideation 0 1 (1%) 1 (1%)
–0·3
–0·32 4 Data are n (%) or mean (SD). *One patient each with cervical dysplasia, ileus,
–0·4 § plasma cell myeloma, and supraventricular arrhythmia. †One patient each with
–0·40 1·96
§ 2 cardiac failure, chronic obstructive pulmonary disease, limb abscess, pain, upper
–0·5
respiratory tract infection. ‡One patient with dyspepsia, gastritis, and hiatus
–0·6 0 hernia. §One patient each with bronchitis, plasma cell myeloma, and worsened
Week 24 Week 24 psoriatic arthropathy. ¶One patient with cardiac failure and two patients with
worsened psoriasis. ||Adverse events identified by investigators as infections.
Figure 2: DISCOVER-1 efficacy up to week 24 (all treated patients, per random group assignment)
Proportion of patients with ACR20 response (note that p=0·0010 for the every 8 weeks group at week 20; A); Table 4: Summary of DISCOVER-1 safety results up to week 24 (all treated
ACR50 response (B); ACR70 response (C); and IGA response (D). IGA response was assessed in patients with at least patients, per treatment received)
3% body surface area of psoriasis and IGA score of at least 2 (mild-to-severe psoriasis) at baseline (n=89 for the every
4 weeks group; n=82 for the every 8 weeks group; and n=78 for the placebo group). Least squares mean changes from
numer­ical differences between the guselkumab groups
baseline in HAQ-DI (E) and SF-36 PCS (F) scores. ACR20=American College of Rheumatology 20% improvement.
ACR50=ACR 50% improvement. ACR70=ACR 70% improvement. HAQ-DI=health assessment questionnaire— and placebo were observed for SF-36 MCS score changes
disability index. IGA=investigator’s global assessment of psoriasis. SF-36 PCS=36-item short-form physical at week 24 (table 2).
component summary. *Unadjusted p<0·05. †p<0·01. ‡p<0·001. §Adjusted p<0·0001. 39 (30%) of 128 patients who received guselkumab every
4 weeks and 29 (23%) of 127 who received guselkumab
patients with baseline HAQ-DI score of 0·35 or more, every 8 weeks had minimal disease activity at week 24
63 (57%) of 110 (every 4 weeks) and 57 (51%) of 112 (every compared with 14 (11%) of 126 in the placebo group
8 weeks) guselkumab-treated patients versus 32 (29%) of (table 2).
110 placebo-treated patients achieved a clinically mean­ An overview of guselkumab pharmacokinetic and
ingful improvement (≥0·35) from baseline in HAQ-DI immunogenicity findings are in the appendix (p 10).
scores (table 2). 71 (56%) of 128 patients receiving guselkumab every
At study outset, patients presented with impaired health- 4 weeks, 68 (54%) of 127 receiving guselkumab every
related quality of life according to the physical and mental 8 weeks, and 75 (60%) of 126 patients receiving placebo
components of the SF-36, with mean PCS scores of reported adverse events up to week 24. Serious adverse
33·8–35·9 and mean MCS scores of 46·5–48·7 across the events and adverse events leading to discontinuation of
groups (USA general population norm is 50·0; table 1). study treatment occurred in small numbers of patients
The least squares mean changes in SF-36 PCS scores in with similar distribution across the groups (table 4).
both guselkumab groups were greater than that in the Among the guselkumab-treated patients, simi­lar propor­
placebo group (both p<0·0001; table 2, figure 2F). Smaller tions of patients who had received previous TNF

1122 www.thelancet.com Vol 395 April 4, 2020


inhibitors (45 [57%] of 79) and those who were TNF
inhibitor-naive (94 [53%] of 176) reported adverse events.
The adverse events reported by at least 5% of patients in
any group were infections (nasopharyngitis and upper
respiratory tract infection) and laboratory parameter
changes (alanine aminotransferase increased and aspar­
tate aminotransferase increased; table 4). Serious infec­
tions occurred in no guselkumab-treated and two (2%) of
126 placebo-treated patients (limb abscess and upper
respiratory tract infection).
Up to week 24, one patient in the placebo group died.
The 50-year-old male patient’s cause of death was cardiac
failure 166 days after the first dose of placebo (no receipt
of guselkumab); this was the only major adverse cardio­
vascular event and the only death reported up to week 24.
One patient was diagnosed with a malignancy up to
week 24. Plasma cell myeloma was reported in a 73-year-
old woman 15 days after the first administration of the
guselkumab every 8 weeks dosing regimen. Clinical
laboratory analysis of a serum sample collected before
the first guselkumab dose indicated increased levels of
γ globulin and M protein, excess free κ light chain
production, and a markedly abnormal κ to λ ratio. Follow-
up testing indicated multiple bone metastases, and the
patient’s diagnosis was refined to stage III multiple
myeloma. The investigator did not consider the event to
be related to guselkumab exposure.
No opportunistic infections or cases of active tuber­
culosis occurred. One patient reported a fungal skin
infection (mycotic infection under right breast at week 16
in a patient receiving guselkumab every 4 weeks; the
infection responded to topical therapy and the patient
continued in the study). No adverse events of inflam­
matory bowel disease were reported.
One patient receiving guselkumab 100 mg every
8 weeks reported suicidal ideation at week 16 and
week 20. The patient had a history of depression or
suicidal ideation and was using antidepressants at
baseline. Suicidal ideation was also reported at week 8 in
a placebo-treated patient with a history of suicidal idea­
tion. Both patients continued in the study. No suicidal
behaviour or self-harming behaviour without suicidal
intent was reported up to week 24.
NCI-CTCAE grade 2 haematological abnormalities
were uncommon and generally similar between the
guselkumab-treated and placebo-treated patients. Among
the two patients in the guselkumab every 4 weeks group
and one patient in the guselkumab every 8 weeks group
with grade 2 neutrophil count decreases (<1·5–1·0 × 10⁹
per L), abnormalities were transient and reversible,
resolved spontaneously without treatment, were not asso­
ciated with infections, and did not result in discontinuation.
Grade 2 lymphocyte count decreases were similar between
guselkumab-treated (five [2%] of 254) and placebo-treated
(three [2%] of 124) patients. The only NCI-CTCAE
grade 3 haematological abnormalities were lymphocyte
decrease (<0·5–0·2 × 10⁹ per L) in three patients receiving
www.thelancet.com Vol 395 April 4, 2020
Articles
guselkumab every 8 weeks; no grade 4 abnormalities
occurred. Two of the three patients with grade 3 lympho­
cytopenia had grade 2 abnormalities (<0·8–0·5 × 10⁹ per L)
before the first guselkumab dose. All instances of grade 3
lymphocytopenia were tran­ sient, with a return to
pretreatment levels at the next visit. No haematological
abnormality in guselkumab-treated patients led to
guselkumab discontinuation, and only one (grade 2)
decreased lymphocyte count was associated with infection
(dental pulpitis or abscess, which resolved).
The proportions of patients with increased alanine
aminotransferase or aspartate aminotransferase concen­
trations reported as adverse events by the investigator
appeared higher in the combined guselkumab than
placebo groups, without evidence of a dose-response
relationship (table 4). However, NCI-CTCAE grades 2–4
alanine aminotransferase or aspartate aminotransferase
increases (more than three times upper limit of normal
[ULN]) were similar between guselkumab (five [2%] of
254 patients had alanine aminotransferase increases
and four [2%] had aspartate aminotransferase increases)
and placebo (two [2%] of 124 patients and four [3%]) and
also demonstrated no apparent relationship to dosing
regimen. No NCI-CTCAE grade 3 (more than five to
20 times ULN) or grade 4 (>20 times ULN) alanine
aminotransferase increases were observed in guselkumab-
treated patients. No grade 4 aspartate amino­transferase
increases (>20 times ULN) were observed, and frequencies
of grade 3 aspartate aminotransferase increases (more
than five to 20 times ULN) were similar between
guselkumab (two [1%]) and placebo (two [2%]) patients.
These laboratory abnormalities were generally transient,
and none resulted in study drug discontinuation.
Discussion
The phase 3 DISCOVER-1 study met its primary end­
point, with both guselkumab 100 mg regimens eliciting
significantly higher ACR20 response rates at week 24
than placebo. Robust treatment effects were also attained
using the more stringent ACR50 response criteria.
Given the complex and variable disease presentation
of psoriatic arthritis, discontinuation or switching of
biologics because of inadequate efficacy or intolerance is
com­mon, as is loss of efficacy over time.3,21 As a human
monoclonal antibody directed against the p19 subunit
of IL-23, guselkumab inhibits IL-23. Inhibition of up­
stream IL-23 signalling reduces downstream production
of cytokines with established (TNFα) or emerging
(IL-17 family) roles in inflammatory conditions such as
psoriasis.22 It has also been postulated that IL-23 blockade,
by transdiffer­entiating Th17 lymphocytes (probably central
effector cells in psoriasis) into T-regulatory cells or Th1 cell
populations,23 interrupts Th17 pathways that contribute to
the chronic inflammation underlying the pathophysiology
of many immune-mediated diseases, including inflam­
matory arthritis, psoriatic arthritis, and psoriasis.24,25
Guselkumab was equally effective in patients who had
1123
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previously received one or two TNF inhibitors, including
in the few patients who inadequately responded to TNF
inhibitors. Guselkumab’s mechanism of action also
differs from that of ustekinumab, which inhibits IL-23 by
targeting the p40 subunit shared by IL-23 and IL-12. Given
that IL-12 has been shown to have a protective role, by
limiting the recruitment of IL-17-producing γδ T cells in
psoriasiform skin inflammation,26 selective targeting of
IL-23 via binding its p19 subunit will offer a novel
mechanism of action to effectively treat the diverse
manifestations of psoriatic arthritis.
Consistent with the robust efficacy demonstrated
by guselkumab in the treatment of psoriasis,19,20 both
guselkumab dosing regimens also elicited significant
improvements in skin psoriasis in this study. Two-thirds of
guselkumab-treated patients with at least 3% body surface
area involvement and IGA score of at least 2 at baseline had
an IGA response (vs 15% for placebo), more than 80% of
such patients had a PASI75 response (vs 14% for placebo),
and more than half had clear or almost clear skin as
assessed by a PASI90 response (vs 12% for placebo), all
highlighting the suitability of guselkumab for patients with
psoriatic arthritis with significant skin disease. Guselkumab
also significantly improved physical function as assessed
by changes in HAQ-DI scores, and most guselkumab-
treated patients with impaired physical function at study
outset had clinically meaningful improvement (≥0·35) in
HAQ-DI scores at week 24. Improvements in psoriasis and
physical func­ tion are particularly important given that
these disease manifestations can lead to depression and
diminished quality of life.27
Guselkumab treatment afforded a significantly improved
physical component of health-related quality of life at
week 24. Smaller numerical differences between both
guselkumab regimens and placebo for improve­ments in
the mental domain of quality of life probably derive from
the milder impairment in mental than physical health at
baseline in this study population.
Notably, at week 24, a quarter of guselkumab-treated
patients (vs 11% for placebo) achieved minimal disease
activity, which integrates independently assessed joint,
skin, and entheseal symptoms with patient-reported pain,
global disease activity, and physical function. International
research groups have identified remission or inactive
disease and, alternatively, low or minimal disease activity
as the principal targets for psoriatic arthritis treatment.28,29
This study was not powered to compare guselkumab
dosing regimens; however, numerically greater improve­
ments were observed with every 4 weeks than every 8 weeks
dosing for some of the clinical efficacy endpoints. In the
larger DISCOVER-2 study18 clinical response rates were
similar for the two guselkumab dosing regimens. Further,
the cumulative evidence derived from additional analyses,
including exposure–response relationship ana­lyses, covari­
ate adjustment for the modest baseline imbalances across
treatment groups, subgroup analyses, and comparisons
within and across the guselkumab phase 2 and phase 3
1124
psoriatic arthritis studies, did not indicate a difference
between the guselkumab every 8 weeks and every 4 weeks
dosing regimens in treating signs and symptoms of
psoriatic arthritis (data not shown).
Guselkumab was generally well tolerated by this
psoriatic arthritis population. No clinically meaningful
differences in safety were observed between the
guselkumab every 4 weeks and every 8 weeks dosing
regimens or between patients with or without previous
TNF inhibitor use. No opportunistic infections or cases
of active tuberculosis and no events of inflammatory
bowel disease occurred. The overall safety profile was
generally consistent with that reported for patients with
psoriasis.19,20,30 Specifically, in an analysis of data from
more than 1800 patients enrolled in two phase 3 psoriasis
studies, guselkumab demonstrated a stable safety profile
up to 100 weeks of treatment, with no signals of concern
related to serious infection, malignancy, major adverse
cardiovascular events, or suicidality,30 and no new safety
signals have been observed in patients with psoriasis
who received guselkumab for up to 4 years in the phase 3
VOYAGE-1 trial.31 Thus, the guselkumab benefit–risk
profile appears favourable for the treatment of patients
with psoriatic arthritis.
Results reported up to week 24 of the DISCOVER-1
study are limited by the relatively short duration of
treatment in the context of a lifelong condition requiring
chronic treatment. Results deriving from up to 1 year
follow-up of the DISCOVER-1 study and 2 years of the
DISCOVER-2 study will be informative in assessing the
maintenance of guselkumab efficacy. Findings related to
patients who demonstrated an inadequate response to
previous TNF inhibitor treat­ment should be interpreted
with caution because of the small size of this study
subgroup. Although the DISCOVER-1 study did not
include imaging assessments, results of the larger
DISCOVER-2 trial indicate that selective IL-23 inhibition
via IL-23 p19 subunit binding with guselkumab every
4 weeks inhibits progression of struc­tural damage in
patients with active psoriatic arthritis.18 DISCOVER-1’s
requirement for screening serum CRP concentration of
at least 0·3 mg/dL might reduce the generalisability of
findings to individuals presenting with milder systemic
inflammation.
In conclusion, week 24 results of this confirmative
phase 3 study provide strong evidence that guselkumab
provides a novel mechanism of action, via targeting the
p19 subunit of IL-23, to treat the diverse clinical mani­
festations of psoriatic arthritis. Notably, guselkumab
might offer an additional treatment option for patients
with active disease despite previous receipt of standard
therapies, including TNF inhibitors.
Contributors
All authors made substantial intellectual contribution to conception and
design, acquisition of data, or analysis and interpretation of data;
drafted the article or revised it critically for important intellectual
content; gave final approval of the version to be published; and agreed to
be accountable for all aspects of the work in ensuring that questions
www.thelancet.com Vol 395 April 4, 2020

related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Declaration of interests
AD has received grants and research support paid to his university
from AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and UCB;
and honoraria or consultation fees from AbbVie, Amgen, Boehringer
Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen,
Novartis, Pfizer, and UCB. PSH has received grants and research support
paid to Leeds Teaching Hospitals Charitable Foundation from AbbVie,
Janssen, and Novartis; and honoraria or consultation fees paid to Leeds
Teaching Hospitals Charitable Foundation from AbbVie, Amgen, Pfizer,
and UCB and to himself from Celgene and Galapagos. W-HB has
received honoraria as a speaker or advisor from AbbVie, Almirall,
Celgene, Janssen, Leo, Lilly, Novartis, and UCB; and he has received a
research grant from Pfizer to investigate the role of JAK inhibition in
psoriasis. APK, ECH, RAS, XLX, SS, PA, BZ, and YZ are employees of
Janssen Research and Development (a subsidiary of Johnson & Johnson)
and own Johnson & Johnson stock or stock options. CTR has received
research funding from Amgen, AbbVie, and UCB; and serves as a
consultant for Amgen, AbbVie, UCB, Janssen, Lilly, Novartis, and Pfizer.
Data sharing
The data sharing policy of Janssen Pharmaceutical Companies of
Johnson & Johnson is available online. Requests for access to the study
data can be submitted through the Yale Open Data Access Project site.
Acknowledgments
We thank Michelle L Perate (consultant funded by Janssen) for assistance
with manuscript preparation and submission and we thank
Diane D Harrison, (consultant funded by Janssen), Soumya D Chakravarty
(Janssen employee), May Shawi (Janssen employee), and Chetan Karyekar
(Janssen employee) for substantive manuscript review.
References
1 Mease PJ, Gladman DD, Collier DH, et al. Etanercept and
methotrexate as monotherapy or in combination for psoriatic
arthritis: primary results from a randomized, controlled phase III
trial. Arthritis Rheumatol 2019; 71: 1112–24.
2 Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis.
N Engl J Med 2017; 376: 957–70.
3 Merola JF, Lockshin B, Mody EA. Switching biologics in the
treatment of psoriatic arthritis. Semin Arthritis Rheum 2017; 47: 29–37.
4 Nash P, Kirkham B, Okada M, et al. Ixekizumab for the treatment
of patients with active psoriatic arthritis and an inadequate response
to tumour necrosis factor inhibitors: results from the 24-week
randomised, double-blind, placebo-controlled period of the
SPIRIT-P2 phase 3 trial. Lancet 2017; 389: 2317–27.
5 Fagerli KM, Lie E, van der Heijde D, et al. Switching between TNF
inhibitors in psoriatic arthritis: data from the NOR-DMARD study.
Ann Rheum Dis 2013; 72: 1840–44.
6 van Kuijk AW, de Groot M, Stapel SO, Dijkmans BA, Wolbink GJ,
Tak PP. Relationship between the clinical response to adalimumab
treatment and serum levels of adalimumab and anti-adalimumab
antibodies in patients with psoriatic arthritis. Ann Rheum Dis 2010;
69: 624–25.
7 Bristol-Myers Squibb. ORENCIA (abatacept). Highlights of
prescribing information. March, 2019. http://packageinserts.bms.
com/pi/pi_orencia.pdf (accessed Oct 15, 2019).
8 Celgene Corporation. OTEZLA (apremilast). Highlights of
prescribing information. July, 2019. https://media.celgene.com/
content/uploads/otezla-pi.pdf (accessed Oct 15, 2019).
9 Pfizer. XELJANZ (tofacitinib). Highlights of prescribing
information. December, 2019. http://labeling.pfizer.com/
ShowLabeling.aspx?id=959 (accessed Oct 15, 2019).
10 Girolomoni G, Altomare G, Ayala F, et al. Safety of anti-TNFα
agents in the treatment of psoriasis and psoriatic arthritis.
Immunopharmacol Immunotoxicol 2012; 34: 548–60.
11 Deodhar A, Mease PJ, McInnes IB, et al. Long-term safety of
secukinumab in patients with moderate-to-severe plaque psoriasis,
psoriatic arthritis, and ankylosing spondylitis: integrated pooled
clinical trial and post-marketing surveillance data. Arthritis Res Ther
2019; 21: 111–21.
www.thelancet.com Vol 395 April 4, 2020
Articles
12 Novartis. COSENTYX (secukinumab). Highlights of prescribing
information. January, 2020. https://www.pharma.us.novartis.com/
sites/www.pharma.us.novartis.com/files/cosentyx.pdf (accessed
Oct 15, 2019).
13 Eli Lilly. TALTZ (ixekizumab). Highlights of prescribing
information. August, 2019. http://pi.lilly.com/us/taltz-uspi.pdf
(accessed Oct 15, 2019).
14 Suzuki E, Mellins ED, Gershwin ME, Nestle FO, Adamopoulos IE.
The IL-23/IL-17 axis in psoriatic arthritis. Autoimmun Rev 2014;
13: 496–502.
15 Girolomoni G, Strohal R, Puig L, et al. The role of IL-23 and the
IL-23/TH 17 immune axis in the pathogenesis and treatment of
psoriasis. J Eur Acad Dermatol Venereol 2017; 31: 1616–26.
16 Deodhar A, Gottlieb AB, Boehncke WH, et al. Efficacy and safety of
guselkumab in patients with active psoriatic arthritis: a randomised,
double-blind, placebo-controlled, phase 2 study. Lancet 2018;
391: 2213–24.
17 Siebert S, Loza MJ, Song Q, McInnes I, Sweet K. Ustekinumab and
guselkumab treatment results in differences in serum IL17A, IL17F
and CRP levels in psoriatic arthritis patients: a comparison from
ustekinumab Ph3 and guselkumab Ph2 programs. Ann Rheum Dis
2019; 78 (suppl 2): A293.
18 Mease PJ, Rahman P, Gottlieb AB, et al. Guselkumab in biologic-
naive patients with active psoriatic arthritis (DISCOVER-2):
a double-blind, randomised, placebo-controlled phase 3 trial. For the data sharing policy see
Lancet 2020; published online March 13. https://doi.org/10.1016/ https://www.janssen.com/
S0140-6736(20)30263-4.
clinical-trials/transparency
19 Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of
guselkumab, an anti-interleukin-23 monoclonal antibody, compared For the Yale Open Data Access
with adalimumab for the continuous treatment of patients with Project site see http://yoda.yale.
moderate to severe psoriasis: results from the phase III, double- edu
blinded, placebo- and active comparator-controlled VOYAGE 1 trial.
J Am Acad Dermatol 2017; 76: 405–17.
20 Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of
guselkumab, an anti-interleukin-23 monoclonal antibody, compared
with adalimumab for the treatment of patients with moderate to
severe psoriasis with randomized withdrawal and retreatment: results
from the phase III, double-blind, placebo- and active comparator-
controlled VOYAGE 2 trial. J Am Acad Dermatol 2017; 76: 418–31.
21 Costa L, Perricone C, Chimenti MS, et al. Switching between
biological treatments in psoriatic arthritis: a review of the evidence.
Drugs R D 2017; 17: 509–22.
22 Brembilla NC, Senra L, Boehncke WH. The IL-17 family of cytokines
in psoriasis: IL-17A and beyond. Front Immunol 2018; 9: 1682.
23 Uttarkar S, Brembilla NC, Boehncke WH. Regulatory cells in the
skin: pathophysiologic role and potential targets for anti-
inflammatory therapies. J Allergy Clin Immunol 2019; 143: 1302–10.
24 Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17
cell effector cytokines in inflammation. Immunity 2008; 28: 454–67.
25 Tato CM, Cua DJ. Reconciling id, ego, and superego within
interleukin-23. Immunol Rev 2008; 226: 103–11.
26 Kulig P, Musiol S, Freiberger SN, et al. IL-12 protects from
psoriasiform skin inflammation. Nat Commun 2016; 7: 13466.
27 Husni ME, Merola JF, Davin S. The psychosocial burden of
psoriatic arthritis. Semin Arthritis Rheum 2017; 47: 351–60.
28 Coates LC, FitzGerald O, Merola JF, et al. Group for Research and
Assessment of Psoriasis and Psoriatic Arthritis/Outcome Measures
in Rheumatology Consensus-based recommendations and research
agenda for use of composite measures and treatment targets in
psoriatic arthritis. Arthritis Rheumatol 2018; 70: 345–55.
29 Smolen JS, Schöls M, Braun J, et al. Treating axial spondyloarthritis
and peripheral spondyloarthritis, especially psoriatic arthritis,
to target: 2017 update of recommendations by an international task
force. Ann Rheum Dis 2018; 77: 3–17.
30 Reich K, Papp KA, Armstrong AW, et al. Safety of guselkumab in
patients with moderate-to-severe psoriasis treated through
100 weeks: a pooled analysis from the randomized VOYAGE 1 and
VOYAGE 2 studies. Br J Dermatol 2019; 180: 1039–49.
31 Griffiths CEM, Papp KA, Song M, et al. Maintenance of response
with up to 4 years of continuous guselkumab treatment:
results from the VOYAGE 1 phase 3 trial. Skin 2019; 3: 202 (abstr).
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