The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Olokizumab versus Placebo or Adalimumab

in Rheumatoid Arthritis
Josef S. Smolen, M.D., Eugen Feist, M.D., Saeed Fatenejad, M.D.,
Sergey A. Grishin, M.D., Ph.D., Elena V. Korneva, M.D., Ph.D.,
Evgeniy L. Nasonov, M.D., Mikhail Y. Samsonov, M.D., Ph.D.,
and Roy M. Fleischmann, M.D., for the CREDO2 Group*​​

A BS T R AC T

BACKGROUND
The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. From the Division of Rheumatology, De-
Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cyto- partment of Medicine 3, Medical Univer-
sity of Vienna, Vienna (J.S.S.); Helios
kine directly, is being tested for the treatment of rheumatoid arthritis. Fachklinik Vogelsang-Gommern, Vogel-
sang-Gommern, Germany (E.F.); SFC
METHODS
Medica, Charlotte, NC (S.F.); R-Pharm
In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we random­ (S.A.G., E.V.K., M.Y.S.), V.A. Nasonova
ly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate Research Institute of Rheumatology
response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg (E.L.N.), and Sechenov Medical Univer-
sity (M.Y.S.) — all in Moscow; and the
every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients University of Texas Southwestern Medi-
continued methotrexate therapy. The primary end point was an American College cal Center at Dallas and Metroplex Clini-
of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and cal Research Center — both in Dallas
(R.M.F.). Dr. Smolen can be contacted
≥20% improvement in three of five other domains) at week 12, with each olokizu­ at ­josef​.­smolen@​­meduniwien​.­ac​.­at or at
mab dose tested for superiority to placebo. We also tested the noninferiority of the Division of Rheumatology, Depart-
each olokizumab dose to adalimumab with respect to the percentage of patients ment of Medicine 3, Medical University
of Vienna, Spitalgasse 23, 1090 Vienna,
with an ACR20 response (noninferiority margin, −12 percentage points in the lower Austria.
boundary of the 97.5% confidence interval for the difference between groups).
*The CREDO2 Group investigators are
RESULTS listed in the Supplementary Appendix,
A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to available at NEJM.org.
receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive N Engl J Med 2022;387:715-26.
placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiv- DOI: 10.1056/NEJMoa2201302
Copyright © 2022 Massachusetts Medical Society.
ing placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo,
25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% re- CME
ceiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; at NEJM.org
97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. place-
bo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of
each olokizumab dose to placebo). Both olokizumab doses were noninferior to
adalimumab with respect to the percentage of patients with an ACR20 response at
week 12 (difference, 3.4 percentage points [97.5% CI, −3.5 to 10.2] with oloki-
zumab every 2 weeks and 4.5 percentage points [97.5% CI, −2.2 to 11.2] with
olokizumab every 4 weeks). Adverse events, most commonly infections, occurred
in approximately 70% of the patients who received olokizumab. Antibodies against
olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks
and in 5.1% of those receiving it every 4 weeks.
CONCLUSIONS
In patients with rheumatoid arthritis who were receiving maintenance methotrex-
ate, olokizumab was superior to placebo and noninferior to adalimumab in pro-
ducing an ACR20 response at 12 weeks. Larger and longer trials are required to
determine the efficacy and safety of olokizumab in patients with rheumatoid ar-
thritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.)
n engl j med 387;8  nejm.org  August 25, 2022 715
 The n e w e ng l a n d j o u r na l
R
heumatoid arthritis is a chronic
autoimmune inflammatory disease char-
acterized by persistent synovitis with syno-
vial cell proliferation and destructive changes in
A Quick Take
bone and cartilage of multiple joints, leading to
is available at joint damage and disability; it is also associated
NEJM.org with premature death.1 Management recommen-
dations suggest meeting the treatment targets of
remission or low disease activity.2,3 If initial treat-
ment with methotrexate fails, the addition of a
biologic disease-modifying antirheumatic drug
or a Janus kinase inhibitor has been suggested.2,3
Two drugs that target the interleukin-6 recep-
tor are currently used to treat rheumatoid arthri-
tis: tocilizumab and sarilumab.2,3 Inhibitors of
the interleukin-6 ligand are not approved for the
treatment of rheumatoid arthritis.4 Two such
inhibitors are sirukumab and clazakizumab;
sirukumab,5-7 but not clazakizumab,8 has been
evaluated in phase 3 trials. Tocilizumab and
sarilumab have been investigated as monothera-
pies in head-to-head trials against adalimumab
monotherapy.9,10 However, monotherapy with
adalimumab is not standard therapy for rheu-
matoid arthritis2,3 because the combination of
adalimumab and methotrexate has been shown
to be superior to monotherapy.11
The cytokine interleukin-6 has multiple func-
tions in cell growth, hematopoiesis, bone metabo-
lism, immune-cell activation, and inflamma-
tion.12 This cytokine has three antigenic sites:
sites 1, 2, and 3.13 Sirukumab and clazakizumab
target site 1, interfering with the binding of inter-
leukin-6 to the cognate interleukin-6 receptor α
in the trimolecular interleukin-6–interleukin-6
receptor–glycoprotein 130 complex. Olokizumab,
another anti–interleukin-6, binds to site 3 and
inhibits the interaction of interleukin-6 and the
interleukin-6–interleukin-6 receptor dimer with
the signal-transducing β-receptor subunit glyco-
protein 130 of the receptor complex.13-16 In this
trial, we evaluated the efficacy and safety of
subcutaneous olokizumab in the treatment of
rheumatoid arthritis.
Me thods
Trial Design and Oversight
This phase 3, multicenter, double-blind, parallel-
group, randomized, placebo- and active-compar-
ator-controlled trial from Clinical Rheumatoid
Arthritis Development for Olokizumab (CREDO2)
was conducted from May 2016 through Novem-
716 n engl j med 387;8  nejm.org  August 25, 2022
of m e dic i n e
ber 2019, at 209 sites in the United States, con-
tinental Europe, the United Kingdom, Asia (South
Korea and Taiwan), and Latin America (Table S1
in the Supplementary Appendix, available with
the full text of this article at NEJM.org). The
trial was designed by the sponsor, R-Pharm (reg-
istered in the United States and Russia), and an
academic advisory board that included authors
who were not employees of R-Pharm. The trial
was conducted in accordance with the ethical
principles of the Declaration of Helsinki and
Good Clinical Practice guidelines and approved
by the institutional review board or ethics com-
mittee at each center. All the patients provided
written informed consent.
R-Pharm or its representatives provided data,
laboratory, and site-monitoring services. All the
authors participated in the company-sponsored
statistical analyses and interpreted the data.
There were confidentiality agreements in place
between the sponsor and the authors; the com-
pany could not delay or interdict publication of
the article. The authors vouch for the veracity
and completeness of the data, for the fidelity of
the trial to the protocol (available at NEJM.org),
and for the complete reporting of adverse events.
Major adverse cardiovascular events (MACE; de-
fined in Table S12 in the Supplementary Appen-
dix) were adjudicated by a cardiovascular adjudi-
cation committee. An independent external data
and safety monitoring board reviewed the safety
throughout the trial.
Inclusion and Exclusion Criteria
Adult patients 18 years of age or older were eli-
gible if they had active rheumatoid arthritis and
fulfilled the American College of Rheumatology
(ACR)–European Alliance of Associations for
Rheumatology (EULAR) 2010 revised classifica-
tion criteria17; had an inadequate response to
methotrexate for at least 12 weeks at a dose of
15 to 25 mg per week (or ≥10 mg per week
[≥7.5 mg per week for patients in South Korea]
if there were unacceptable adverse events at
higher doses), with a stable dose and adminis-
tration route for at least 6 weeks before screen-
ing; and had at least 6 swollen joints (of 66 joints
assessed), at least 6 tender joints (of 68 joints
assessed), and an elevated C-reactive protein
(CRP) level (>6 mg per liter). (Details on the in-
clusion and exclusion criteria are provided in the
Methods section in the Supplementary Appendix
and in the protocol.)
 Olokizumab in Rheumatoid Arthritis
Randomization and Blinding
Patients were randomly assigned in a 2:2:2:1 ratio
to receive subcutaneous injections of 64 mg of
olokizumab every 2 or 4 weeks, 40 mg of adalimu­
mab (Humira, AbbVie) every 2 weeks, or placebo
every 2 weeks for 24 weeks; all the patients con-
tinued methotrexate therapy. To maintain blind-
ing, patients who received olokizumab every
4 weeks alternated between injections of olokizu­
mab or placebo every 2 weeks. After the double-
blind treatment period of 24 weeks, patients
could enter an open-label extension study or a
safety follow-up period of 20 weeks, at their
discretion. All the patients, investigators, clini-
cal site staff, and sponsor staff directly involved
in the trial were unaware of the trial-group as-
signments. (Details on blinding are provided in
the Methods section in the Supplementary Ap-
pendix.)
Rescue Medication
To allow a 24-week duration of the placebo con-
trol in the trial to be consistent with ethical
treatment guidelines, all the patients who did
not have a response (defined as those who did
not have a decrease of ≥20% in both the swollen-
joint count and the tender-joint count) at week
14 were prescribed rescue medication (sulfasala-
zine, hydroxychloroquine, or both) in addition to
assigned treatment including methotrexate, ir-
respective of trial-group assignment. (Details on
rescue medication are provided in the Methods
section in the Supplementary Appendix.)
End Points
The primary efficacy end point was an improve-
ment of at least 20% in the ACR response criteria
(ACR20 response) at week 12, with each olokizu­
mab dose tested for superiority to placebo. An
ACR20 response was defined as a decrease of
20% or more in both the tender-joint count and
the swollen-joint count and an improvement of
20% or more in at least three of the following
five measures: a patient’s global assessment of
disease activity, a patient’s assessment of pain,
and a physician’s global assessment of disease
activity (with all three evaluations measured on
a visual-analogue scale of 0 to 100 mm, with
higher values indicating greater disease activi-
ty or pain); patient function according to the
Health Assessment Questionnaire–Disability In-
dex (HAQ-DI) score (range, 0 to 3, with higher
scores indicating greater disability); and the
n engl j med 387;8  nejm.org  August 25, 2022
level of acute-phase reactants (as measured by
the CRP level).18
Multiplicity-controlled, ranked secondary end
points were the noninferiority of each olokizu­
mab dose to adalimumab with respect to an
ACR20 response at week 12, the percentage of
patients with a Disease Activity Score for 28 joints
based on the CRP level (DAS28-CRP; range, 0 to
9.4, with higher scores indicating more disease
activity)19 of less than 3.2 at week 12 to test the
superiority of olokizumab to placebo and the
noninferiority of olokizumab to adalimumab,
the decrease (indicating improvement) in the
HAQ-DI score from baseline to week 12, an im-
provement of at least 50% in the ACR response
criteria (ACR50 response) at week 24, and a
Clinical Disease Activity Index (CDAI) score of
2.8 or less (range, 0 to 76, with higher scores
indicating greater disease activity and a score of
≤2.8 indicating remission) at week 24. Other
exploratory efficacy end points were prespeci-
fied but not included in the hierarchical analysis,
and the widths of confidence intervals for differ-
ences between groups were not adjusted for
multiple comparisons. (Details on end points
are provided in the Methods section in the Sup-
plementary Appendix and in Table S4.)
Safety monitoring included assessment of ad-
verse events that first occurred or worsened in
severity after the first dose of a trial agent, as-
sessment of serious adverse events, and regular
centrally performed laboratory tests. Adverse
events of special interest were serious infections
(including opportunistic infections), systemic in-
jection reactions (including anaphylaxis), cancers,
autoimmune disorders, gastrointestinal perfora-
tions, elevation of lipid levels, cytopenias, demy-
elination in the peripheral or central nervous
system, potential hepatotoxic effects, and adju-
dicated MACE. Plasma antidrug antibody titers
against olokizumab were determined by means
of electrochemiluminescence assay. A cell-based
assay was used to detect neutralizing antidrug
antibodies.
Statistical Analysis
To confirm a significant treatment effect for at
least one olokizumab dose regimen, we estimated
that a sample size of 1575 patients randomly
assigned in a 2:2:2:1 ratio was needed to ensure
sufficient discriminatory power: 100% for test-
ing the primary hypothesis, 92% for testing the
noninferiority of both olokizumab doses to
717
 The n e w e ng l a n d j o u r na l
adalimumab with respect to an ACR20 response
at week 12, and 92% for testing the superiority
of olokizumab to placebo and 88% for testing
the noninferiority of olokizumab to adalimumab
with respect to a DAS28-CRP of less than 3.2 at
week 12. The primary analysis was performed in
the intention-to-treat population, defined as all the
patients who underwent randomization. The safe-
ty population included all the patients who re-
ceived at least one dose of a trial agent.
A gate-keeping strategy with fixed-order hy-
pothesis testing was used for the primary and
secondary end points within each olokizumab
dose regimen independently (see Fig. S1 and the
statistical analysis plan, available with the pro-
tocol). The following hypothesis tests were in-
cluded in the multiplicity control procedure with
97.5% confidence intervals: the superiority of
each olokizumab dose to placebo with respect
to an ACR20 response at week 12 (primary end
point), the noninferiority of each olokizumab
dose to adalimumab with respect to an ACR20
response at week 12, the superiority of each
olokizumab dose to placebo and the noninferi-
ority of each olokizumab dose to adalimumab
with respect to a DAS28-CRP of less than 3.2 at
week 12, and the superiority of each olokizumab
dose to placebo with respect to the decrease in
the HAQ-DI score at week 12, an ACR50 re-
sponse at week 24, and a CDAI score of 2.8 or
less (remission) at week 24. The test for superior-
ity of adalimumab to placebo with respect to an
ACR20 response at week 12 was not included in
the multiplicity control strategy and was carried
out with the use of a one-sided alpha level of
0.025. To control the overall type I error rate at
a one-sided alpha level of 0.025, Bonferroni
adjustment was used in the analysis of each
olokizumab dose as compared with placebo (i.e.,
one-sided alpha level of 0.0125 for each dose) to
preserve the familywise error rate.
All efficacy end points that were binary in
nature, including the primary efficacy end point,
were analyzed with the use of two-by-two chi-
square tests for equality of proportions for each
olokizumab group as compared with the placebo
group and for testing for superiority of adalimu­
mab to placebo. Noninferiority testing for each
olokizumab dose as compared with adalimumab
with respect to an ACR20 response and a DAS28-
CRP of less than 3.2 used a 97.5% two-sided
confidence interval for the difference between
proportions with the use of the Newcombe hy-
718 n engl j med 387;8  nejm.org  August 25, 2022
of m e dic i n e
brid score method, with protocol-specified non-
inferiority margins of −12 percentage points and
−7.5 percentage points, respectively. Noninferi-
ority would be achieved if the lower limit of the
97.5% confidence interval was greater than the
noninferiority margin.
For selection of the noninferiority margins,
the following assumptions were used: in a meta-
analysis of two pivotal clinical trials for registra-
tion of adalimumab,20,21 the difference in the
percentage of patients with an ACR20 response
at week 12 between adalimumab in combination
with methotrexate (280 patients) and placebo in
combination with methotrexate (262 patients)
was 35.0 percentage points (95% confidence in-
terval [CI], 27.3 to 42.6). Therefore, 27.3 percent-
age points was estimated to be the absolute
largest noninferiority margin that could be justi-
fied. In the determination of a clinically mean-
ingful effect, we assumed that 55% of the pa-
tients receiving adalimumab would have an ACR20
response at week 12 and that a minimum of 43%
of those receiving olokizumab would have such
a response. As a result, a noninferiority margin
of −12 percentage points for the percentage of
patients with an ACR20 response at week 12 was
used in this trial.
In a meta-analysis of two clinical trials of
adalimumab,22,23 the difference in the percentage
of patients with a DAS28-CRP of less than 3.2 at
week 12 between adalimumab plus methotrex-
ate (537 patients) and placebo plus methotrexate
(688 patients) was equal to 20.0 percentage
points (95% CI, 15.3 to 24.6). Therefore, 15.3
percentage points was the absolute largest non-
inferiority margin that could be justified. In the
determination of a clinically meaningful effect,
we assumed that 27% of the patients receiving
adalimumab would have a DAS28-CRP of less
than 3.2 at week 12 and that a minimum of
19.5% of those receiving olokizumab would have
such a response. As a result, we used a noninfe-
riority margin of −7.5 percentage points for the
percentage of patients with a DAS28-CRP of less
than 3.2 at week 12. (Details on noninferiority
testing are provided in the Methods section in
the Supplementary Appendix and in Fig. S2.)
For analyses of binary variables, discontinua-
tion of a trial agent was defined as a nonre-
sponse. In case of missing visits or assessments
not performed for reasons other than discon-
tinuation of a trial agent, all missing data were
imputed with the use of information obtained in
 Olokizumab in Rheumatoid Arthritis
surrounding visits (as discussed in the Methods
section in the Supplementary Appendix). Con-
tinuous efficacy end points were assessed with
the use of an analysis of covariance model, with
adjustment for the baseline value of the corre-
sponding variable. In the analyses of these end
points, patients who discontinued a trial agent
prematurely but remained in the trial were in-
cluded through the use of collected measure-
ments, including those from assessments after
discontinuation of a trial agent. In case of miss-
ing values, return-to-baseline values were imple-
mented with the use of multiple imputation,
with accounting for the uncertainty of missing
data, according to the methods of Rubin for
continuous end points (see the Methods section
in the Supplementary Appendix).24 Protocol-
specified statistical analyses were performed
with the use of SAS software, version 9.4 or
higher (SAS Institute).
R e sult s
Patient Characteristics
A total of 1648 patients were randomly assigned
to receive 64 mg of olokizumab every 2 weeks
(464 patients), 64 mg of olokizumab every
4 weeks (479 patients), 40 mg of adalimumab
every 2 weeks (462 patients), or placebo (243
patients). The safety population consisted of
1645 patients; 3 patients underwent randomiza-
tion but did not receive the assigned trial agent
(Fig. 1). The trial groups were similar with re-
spect to the demographic and clinical character-
istics of the patients at baseline (Table 1). Sex,
the mean age of the patients, and disease dura-
tion were representative of a European popula-
tion of patients with rheumatoid arthritis (the
percentage of Black patients [3 to 5%] was not
representative for the United States, and the
percentage of Asian patients [1.5%] was not rep-
resentative for Asian countries) (Tables 1, S1,
and S3). Missing data are presented in Table S5,
and explanations are provided in the Methods
section in the Supplementary Appendix.
A total of 89.7% of the patients (1479) com-
pleted the 24-week treatment period: 90.7%
(421) with olokizumab every 2 weeks, 91.2% (437)
with olokizumab every 4 weeks, 89.4% (413) with
adalimumab, and 85.6% (208) with placebo
(94.4%, 93.8%, 92.6%, and 89.3%, respectively,
completed week 12). The most common reason
for discontinuation of a trial agent was an ad-
n engl j med 387;8  nejm.org  August 25, 2022
verse event in the active-treatment groups (with
a similar percentage of patients in each group)
and withdrawal from the trial in the placebo
group (Fig. 1 and Table S2).
Primary End Point
At week 12, the proportion of patients with an
ACR20 response was 326 of 464 (70.3%) with
olokizumab every 2 weeks, 342 of 479 (71.4%)
with olokizumab every 4 weeks, and 309 of 462
(66.9%) with adalimumab, as compared with
108 of 243 (44.4%) with placebo (adjusted differ-
ence vs. placebo, 25.9 percentage points [97.5%
CI, 17.1 to 34.1], 27.0 percentage points [97.5%
CI, 18.3 to 35.2], and 22.5 percentage points
[95% CI, 14.8 to 29.8], respectively; P<0.001 for
all comparisons) (Table 2). As shown in Fig-
ure 2A, the percentage of patients with an ACR20
response in the olokizumab groups separated
from that in the placebo group by week 2 and
increased throughout the trial, but these obser-
vations were not formally analyzed. The percent-
age in the olokizumab groups was similar to
that in the adalimumab group.
Secondary End Points
Both olokizumab doses were noninferior to
adalimumab with respect to the percentage of
patients with an ACR20 response according
to the prespecified margin (difference, 3.4 per-
centage points [97.5% CI, −3.5 to 10.2] with
olokizumab every 2 weeks and 4.5 percentage
points [97.5% CI, −2.2 to 11.2] with olokizumab
every 4 weeks) (Table 2). The percentage of pa-
tients with a DAS28-CRP of less than 3.2 at week
12 was 45.3% with olokizumab every 2 weeks,
45.7% with olokizumab every 4 weeks, and 38.3%
with adalimumab, as compared with 12.8% with
placebo (adjusted difference vs. placebo, 32.5
percentage points [97.5% CI, 25.0 to 39.1], 32.9
percentage points [97.5% CI, 25.5 to 39.5], and
25.5 percentage points [95% CI, 19.1 to 31.3],
respectively; P<0.001 for all comparisons) (Ta-
ble 2 and Fig. 2B).
Improvement in physical function as assessed
with the use of the HAQ-DI score was greater at
week 12 in both olokizumab groups than in the
placebo group (P<0.001 for both comparisons);
improvement in the adalimumab group was
similar to that in the olokizumab groups (Ta-
ble 2 and Fig. 2C). The percentage of patients
with an ACR50 response at week 24 was 50.4%
with olokizumab every 2 weeks and 50.1% with
719
 The n e w e ng l a n d j o u r na l of m e dic i n e

3359 Patients were assessed for eligibility

1711 Had screening failure

1648 Underwent randomization

464 Were assigned to receive
olokizumab every 2 wk plus
methotrexate
462 (99.6%) Received assigned
intervention
2 (0.4%) Did not receive
assigned intervention
479 Were assigned to receive
olokizumab every 4 wk plus
methotrexate
478 (99.8%) Received assigned
intervention
1 (0.2%) Did not receive
assigned intervention
462 Were assigned to receive
adalimumab every 2 wk plus
methotrexate
462 (100%) Received assigned
intervention
243 Were assigned to receive
placebo plus methotrexate
243 (100%) Received assigned
intervention

41 (8.8%) Discontinued trial
23 (5.0%) Had adverse event
1 (0.2%) Had protocol violation
with respect to eligibility criteria
12 (2.6%) Withdrew
1 Decided there was a lack
of efficacy
8 Withdrew consent
3 Had other reason
5 (1.1%) Were lost to follow-up
41 (8.6%) Discontinued trial
28 (5.8%) Had adverse event
2 (0.4%) Had protocol violation
with respect to eligibility criteria
8 (1.7%) Withdrew
1 Decided there was a lack
of efficacy
4 Withdrew consent
3 Had other reason
1 (0.2%) Was withdrawn by
sponsor
2 (0.4%) Had other reason
49 (10.6%) Discontinued trial 35 (14.4%) Discontinued trial
1 (0.2%) Had investigator who 3 (1.2%) Had investigator who
decided there was a lack of decided there was a lack of
efficacy efficacy
26 (5.6%) Had adverse event 9 (3.7%) Had adverse event
8 (1.7%) Had protocol violation 4 (1.6%) Had protocol violation
1 Had consistent nonadherence with respect to eligibility criteria
to trial drug dosing 15 (6.2%) Withdrew
1 Had consistent nonadherence 5 Decided there was a lack
to trial procedures of efficacy
2 Received prohibited concomi- 8 Withdrew consent
tant medications 2 Had other reason
4 Had violation of eligibility 4 (1.6%) Were lost to follow-up
criteria
8 (1.7%) Withdrew
5 Decided there was a lack
of efficacy
3 Withdrew consent
2 (0.4%) Were lost to follow-up
1 (0.2%) Was withdrawn by
sponsor
1 (0.2%) Had trial terminated
by sponsor or investigator
2 (0.4%) Had other reason

421 (90.7%) Completed treatment 437 (91.2%) Completed treatment 413 (89.4%) Completed treatment 208 (85.6%) Completed treatment
421 (90.7%) Completed trial 443 (92.5%) Completed trial 412 (89.2%) Completed trial 207 (85.2%) Completed trial

463 (99.8%) Were included in the 477 (99.6%) Were included in the 462 (100%) Were included in the 243 (100%) Were included in the
safety analysis safety analysis safety analysis safety analysis

Figure 1. Screening, Randomization, and Follow-up.

Patients who discontinued a trial agent early and entered the safety follow-up period were considered to have completed the trial if they
performed follow-up visits. The intention-to-treat population was used for analyses, so all the patients who were randomly assigned to a
trial group were included in the analyses. Therefore, the number of patients who completed the trial was higher than the number of pa-
tients who completed treatment.

olokizumab every 4 weeks, as compared with
22.6% with placebo (adjusted difference vs. pla-
cebo, 27.8 percentage points [97.5% CI, 19.5
to 35.3] and 27.5 percentage points [97.5% CI,
19.2 to 34.9], respectively; P<0.001 for both com-
parisons) (Table 2 and Fig. 2D). The percentage
of patients with remission as assessed by the
ACR-EULAR index-based remission definition25 of
a CDAI score of 2.8 or less at week 24 was higher
with olokizumab every 2 weeks (11.2%) and every

720 n engl j med 387;8  nejm.org  August 25, 2022

 Olokizumab in Rheumatoid Arthritis

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline (Intention-to-Treat Population).*

Olokizumab Olokizumab Adalimumab

Every 2 Wk Every 4 Wk Every 2 Wk Placebo
Characteristics (N = 464) (N = 479) (N = 462) (N = 243)
Age — yr 53.3±11.9 53.7±12.1 54.3±12.3 54.7±11.9
Female sex — no. (%) 352 (75.9) 378 (78.9) 363 (78.6) 190 (78.2)
Race — no. (%)†
Asian 10 (2.2) 6 (1.3) 4 (0.9) 5 (2.1)
Black 20 (4.3) 15 (3.1) 23 (5.0) 11 (4.5)
White 382 (82.3) 406 (84.8) 385 (83.3) 203 (83.5)
Other or mixed race 52 (11.2) 52 (10.9) 50 (10.8) 24 (9.9)
Mean duration of rheumatoid arthritis (range) — yr 7.5 (0.3–38.9) 7.4 (0.3–40.5) 7.4 (0.3–40.2) 6.9 (0.3–42.5)
Methotrexate dose — mg‡ 17.0±4.10 17.2±4.0 17.3±4.0 17.1±4.0
Duration of previous methotrexate use — mo 43.4±52.8 44.0±49.6 46.5±55.5 45.0±53.2
Glucocorticoid use — no./total no. (%) 287/463 (62.0) 285/477 (59.7) 266/462 (57.6) 155/243 (63.8)
Prednisone dose or equivalent — mg 5.7±2.5 5.7±2.1 5.8±2.1 5.7±2.3
Body-mass index§ 28.7±6.1 28.7±6.3 28.5±6.2 28.6±6.6
Positivity for rheumatoid factor — no. (%)¶ 352 (75.9) 355 (74.1) 343 (74.2) 181 (74.5)
Positivity for anti–cyclic citrullinated peptide 355 (76.5) 361 (75.4) 324 (70.1) 188 (77.4)
— no. (%)‖
C-reactive protein — mg/liter** 19.0±21.1 18.4±18.6 18.6±18.5 17.1±17.2
Tender-joint count†† 23.9±12.5 23.6±12.9 23.9±12.7 22.4±12.3
Swollen-joint count†† 14.6±7.3 15.4±8.8 15.5±8.0 14.9±8.5
DAS28-CRP‡‡ 5.9±0.8 5.8±0.8 5.9±0.9 5.8±0.8
CDAI score§§ 39.4±11.0 39.4±11.3 39.3±11.7 38.7±11.4
HAQ-DI score¶¶ 1.73±0.58 1.69±0.60 1.72±0.57 1.71±0.62
Patient’s global assessment of disease activity‖‖ 67.5±20.2 66.8±20.9 66.7±21.0 67.4±20.0
Patient’s assessment of pain‖‖ 68.4±20.6 67.1±21.0 66.8±21.5 66.5±20.7
Physician’s global assessment of disease activity‖‖ 66.2±16.1 66.8±15.9 65.2±17.1 65.5±16.4

* Plus–minus values are means ±SD. Patients in the olokizumab groups received 64 mg every 2 or 4 weeks, and those in the adalimumab
group received 40 mg every 2 weeks. Percentages may not total 100 because of rounding.
† Race was reported by the patients.
‡ All the patients received methotrexate in addition to olokizumab, adalimumab, or placebo.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Positivity for rheumatoid factor was defined as a level of at least 20 IU per milliliter.
‖ Positivity for anti–cyclic citrullinated peptide was defined as a level of more than 10 IU per milliliter.
** The upper limit of the normal range is 6 mg per liter.
†† A total of 68 joints were assessed for the tender-joint count, and 66 joints were assessed for the swollen-joint count.
‡‡ Values for the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP) range from 0 to 9.4, with higher
scores indicating more disease activity.
§§ Clinical Disease Activity Index (CDAI) scores range from 0 to 76, with higher scores indicating greater disease activity.
¶¶ Health Assessment Questionnaire–Disability Index (HAQ-DI) scores range from 0 to 3, with higher scores indicating greater disability.
‖‖ This evaluation was based on a visual-analogue scale of 0 to 100 mm, with higher values indicating greater disease activity or pain.

4 weeks (12.1%) than with placebo (4.1%) (ad-
justed difference vs. placebo, 7.1 percentage points
[97.5% CI, 2.2 to 11.3] and 8.0 percentage points
[97.5% CI, 3.1 to 12.3], respectively; P<0.001 for
both comparisons); the percentage in the adalimu­
mab group (13.0%) was similar to that in the
olokizumab groups (Table 2 and Fig. 2E).
The results for other efficacy end points and
components of the ACR response criteria with
olokizumab as compared with placebo were
generally in the same direction as those for the
primary end-point analysis (Table S10 and Fig.
S3). Exploratory subgroup analyses of the ACR20
response are shown in Tables S7, S8, and S9.

n engl j med 387;8  nejm.org  August 25, 2022 721

 Table 2. Main Efficacy Results (Intention-to-Treat Population).*

722
Olokizumab Olokizumab Adalimumab
Every 2 Wk Every 4 Wk Every 2 Wk Placebo
End Point (N = 464) (N = 479) (N = 462) (N = 243)
Primary end point
ACR20 response at wk 12 — no. (%)† 326 (70.3) 342 (71.4) 309 (66.9) 108 (44.4)
Difference vs. placebo (CI) — percentage points‡ 25.9 (17.1 to 34.1)§ 27.0 (18.3 to 35.2)§ 22.5 (14.8 to 29.8)§
Secondary end points
ACR20 response at wk 12 — no. (%)† 326 (70.3) 342 (71.4) 309 (66.9) 108 (44.4)
Difference vs. adalimumab (97.5% CI) — percentage points¶ 3.4 (−3.5 to 10.2) 4.5 (−2.2 to 11.2)
DAS28-CRP of <3.2 at wk 12 — no. (%) 210 (45.3) 219 (45.7) 177 (38.3)   31 (12.8)
Difference vs. placebo (CI) — percentage points‡ 32.5 (25.0 to 39.1)§ 32.9 (25.5 to 39.5)§ 25.5 (19.1 to 31.3)§
Difference vs. adalimumab (97.5% CI) — percentage points¶ 7.0 (−0.3 to 14.1) 7.4 (0.2 to 14.5)
The

Change in HAQ-DI score from baseline to wk 12 −0.64±0.03 −0.61±0.03 −0.61±0.03 −0.42±0.04

Least-squares mean difference vs. placebo (CI)‡ −0.22 (−0.33 to −0.12)§ −0.19 (−0.29 to −0.09)§ −0.19 (−0.28 to −0.10)§
Least-squares mean difference vs. adalimumab (97.5% CI) −0.03 (−0.12 to 0.05) 0.00 (−0.08 to 0.08)
ACR50 response at wk 24 — no. (%)‖ 234 (50.4) 240 (50.1) 214 (46.3)   55 (22.6)
Difference vs. placebo (CI) — percentage points‡ 27.8 (19.5 to 35.3)§ 27.5 (19.2 to 34.9)§ 23.7 (16.5 to 30.3)§
Difference vs. adalimumab (97.5% CI) — percentage points 4.1 (−3.2 to 11.4) 3.8 (−3.5 to 11.0)
CDAI score of ≤2.8 at wk 24 — no. (%)** 52 (11.2) 58 (12.1) 60 (13.0) 10 (4.1)
Difference vs. placebo (CI) — percentage points‡ 7.1 (2.2 to 11.3)§ 8.0 (3.1 to 12.3)§ 8.9 (4.6 to 12.7)§
Difference vs. adalimumab (97.5% CI) — percentage points −1.8 (−8.1 to 4.7) −0.9 (−5.8 to 4.0)
n e w e ng l a n d j o u r na l
of

* Plus–minus values are means ±SE. Patients who discontinued a trial agent or did not complete the trial were considered to have not had a response.
† An American College of Rheumatology 20 (ACR20) response was defined as a decrease of 20% or more in both the tender-joint count and the swollen-joint count and an improve-
ment of 20% or more in at least three of five other domains.
‡ A 97.5% CI was calculated for comparisons between olokizumab and placebo, and a 95% CI was calculated for the comparison between adalimumab and placebo.

n engl j med 387;8  nejm.org  August 25, 2022

§ P<0.001 for the comparison with placebo.
¶ Noninferiority for each olokizumab dose to adalimumab was achieved if the lower limit of the 97.5% CI was greater than the protocol-defined noninferiority margin of −12 percentage
m e dic i n e

points for an ACR20 response at week 12 and −7.5 percentage points for a DAS28-CRP of less than 3.2 at week 12.
‖ An American College of Rheumatology 50 (ACR50) response was defined as a decrease of 50% or more in both the tender-joint count and the swollen-joint count and an improve-
ment of 50% or more in at least three of five other domains.
** A CDAI score of 2.8 or less was considered to indicate remission.
 Olokizumab in Rheumatoid Arthritis

A ACR20 Response
100
90
80 71.4 74.1
70.3
Percent of Patients

70 71.4
69.0 Olokizumab every 2 wk
60 66.9
Olokizumab every 4 wk
50
46.5 Adalimumab every 2 wk
40 44.4
Placebo
30
20
10
0
0 4 8 12 16 20 24
Weeks since Baseline

B DAS28-CRP of <3.2 C Change in HAQ-DI Score

100 0.0
90 −0.1

Mean Change from Baseline

80
−0.2
Percent of Patients

70
60 −0.3
53.9 −0.42
50 52.2 −0.4
45.7 46.1 −0.45
40 45.3 −0.5
30 −0.60
−0.61
38.3 −0.6
20 21.8 −0.63
–0.65 −0.67
10 −0.7 −0.71
12.8
0 −0.8
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Weeks since Baseline Weeks since Baseline

D ACR50 Response E CDAI Score of ≤2.8

100 100
90 90
80 80
Percent of Patients
Percent of Patients

70 70
60 60
50.4
50 42.8 50.1 50
40.9 46.3
40 40
30 39.2 30
20 22.6 20 8.0 13.0
7.8 3.3 12.1
10 15.6 10 7.7 11.2
4.1
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Weeks since Baseline Weeks since Baseline

Figure 2. Key Efficacy End Points (Intention-to-Treat Population).

Patients who discontinued a trial agent or did not complete the trial were considered to have not had a response.
An American College of Rheumatology 20 (ACR20) response (Panel A) was defined as a decrease of 20% or more in
both the tender-joint count and the swollen-joint count and an improvement of 20% or more in at least three of five
other domains. Values for the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP)
(Panel B) range from 0 to 9.4, with higher scores indicating more disease activity. Health Assessment Questionnaire–
Disability Index (HAQ-DI) scores (Panel C) range from 0 to 3, with higher scores indicating greater disability. An
American College of Rheumatology 50 (ACR50) response (Panel D) was defined as a decrease of 50% or more in
both the tender-joint count and the swollen-joint count and an improvement of 50% or more in at least three of five
other domains. Clinical Disease Activity Index (CDAI) scores (Panel E) range from 0 to 76, with higher scores indi-
cating greater disease activity; a score of 2.8 or less was considered to indicate remission.

n engl j med 387;8 nejm.org August 25, 2022 723

 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Adverse Events and Serious Adverse Events (Safety Population).*

Olokizumab Olokizumab Adalimumab

Every 2 Wk Every 4 Wk Every 2 Wk Placebo
Event (N = 463) (N = 477) (N = 462) (N = 243)

number of patients with event (percent)

At least one adverse event 324 (70.0) 338 (70.9) 302 (65.4) 154 (63.4)
Infection 140 (30.2) 162 (34.0) 148 (32.0) 84 (34.6)
Cancer 2 (0.4) 3 (0.6) 3 (0.6) 3 (1.2)
At least one potential MACE† 4 (0.9) 2 (0.4) 2 (0.4) 1 (0.4)
Pulmonary embolism 1 (0.2) 0 0 0
Adverse event leading to discontinuation of trial agent 21 (4.5) 30 (6.3) 26 (5.6) 9 (3.7)
At least one key serious adverse event 22 (4.8) 20 (4.2) 26 (5.6) 12 (4.9)
Serious infection‡ 6 (1.3) 7 (1.5) 16 (3.5) 4 (1.6)
Serious adverse event leading to death§ 3 (0.6) 2 (0.4) 1 (0.2) 1 (0.4)

* Shown are adverse events that first occurred or worsened in severity after the first dose of a trial agent.
† Major adverse cardiovascular events (MACE) were as follows: among patients receiving olokizumab every 2 weeks,
nonfatal stroke or transient ischemic attack in three patients (0.6%) and fatal stroke and death due to undetermined
cause in one patient each (0.2%); among patients receiving olokizumab every 4 weeks, death from cardiovascular
causes and nonfatal myocardial infarction in one patient each (0.2%); among patients receiving adalimumab, nonfatal
stroke or transient ischemic attack in two patients (0.4%); and among patients receiving placebo, death from cardio-
vascular causes in one patient (0.4%).
‡ Among patients receiving olokizumab every 2 weeks, serious infections were pneumonia, sepsis, erysipelas, interver-
tebral discitis, abdominal abscess, and septic shock in one patient each (0.2%). Among patients receiving olokizumab
every 4 weeks, serious infections were cellulitis in two patients (0.4%) and pneumonia, sepsis, erysipelas, streptococcal
pharyngitis, and pulmonary tuberculosis in one patient each (0.2%). Details on serious infections among patients re-
ceiving adalimumab or placebo are provided in Tables S11, S12, and S13 in the Supplementary Appendix.
§ Serious adverse events leading to death were as follows: among patients receiving olokizumab every 2 weeks, stroke,
sepsis, and septic shock in one patient each (0.2%); among patients receiving olokizumab every 4 weeks, sepsis and
myocardial infarction in one patient each (0.2%); among patients receiving adalimumab, sepsis in one patient (0.2%);
and among patients receiving placebo, sudden death in one patient (0.4%).

Safety events were infections, which occurred in 1.3%,

A total of 1118 patients (68.0%) had adverse
events that first occurred or worsened in sever-
ity after the first dose of a trial agent (Tables 3
and S11). The most common adverse events were
infections, with nasopharyngitis, upper respira-
tory tract infections, and urinary tract infections
reported most frequently. In general, adverse
events were mild to moderate in severity as as-
sessed by the investigators. Adverse events
leading to discontinuation of a trial agent were
reported in 4.5% of the patients receiving olokizu­
mab every 2 weeks, 6.3% of those receiving
olokizumab every 4 weeks, 5.6% of those receiv-
ing adalimumab, and 3.7% of those receiving
placebo.
The incidence of serious adverse events was
similar across the trial groups: 4.8% with olokizu­
mab every 2 weeks, 4.2% with olokizumab every
4 weeks, 5.6% with adalimumab, and 4.9% with
placebo. The most frequently reported serious
1.5%, 3.5%, and 1.6%, respectively. The types of
serious infections are detailed in Tables 3 and
S12. Adverse events leading to death were re-
ported in three patients receiving olokizumab
every 2 weeks, two patients receiving olokizu­
mab every 4 weeks, one patient receiving adalimu­
mab, and one patient receiving placebo (Tables 3
and S12). Further details, including changes in
laboratory values, are provided in Figure S5 and
Tables S13 and S14.
Immunogenicity
Positive results for antidrug antibody tests at any
time after baseline were reported in 17 of 443
patients (3.8%) receiving olokizumab every 2 weeks
and in 23 of 454 patients (5.1%) receiving olokizu­
mab every 4 weeks. Two patients, both of whom
were receiving olokizumab every 4 weeks, were
positive for neutralizing antibodies, and 1 of these
2 did not have an ACR20 response at week 12.

724 n engl j med 387;8  nejm.org  August 25, 2022

 Olokizumab in Rheumatoid Arthritis
Discussion
Olokizumab is a direct inhibitor of the interleu-
kin-6 ligand, which differentiates it from the
currently approved interleukin-6 receptor inhibi-
tors that bind to its receptor.13,26 In this trial
involving patients with rheumatoid arthritis,
olokizumab plus methotrexate was superior to
placebo plus methotrexate with respect to an
ACR20 response at week 12 and was noninferior
to the combination of adalimumab and metho-
trexate. Although there was no prespecified plan
to test the superiority of olokizumab to adalimu­
mab with respect to an ACR20 response, the
confidence interval for the differences between
groups included zero.
Olokizumab was also superior to placebo
with respect to an ACR50 response (secondary
end point). Because the secondary end-point
measure of DAS28-CRP includes the acute-
phase reactant CRP in its calculation and be-
cause interleukin-6 inhibition interferes with
CRP production more directly than an anti–tumor
necrosis factor (TNF) drug such as adalimu­
mab, it is not an ideal measure for a compari-
son with a TNF inhibitor but was evaluated on
regulatory request. As a prespecified end point,
a CDAI score of 2.8 or less, a validated measure
of remission in rheumatoid arthritis recom-
mended by the ACR and EULAR,25 occurred
more frequently in the two olokizumab groups
and the adalimumab group than in the placebo
group; it does not include CRP and may be a
more appropriate measure for anti–interleu-
kin-6 or anti–interleukin-6 receptor biologics
than those including acute-phase reactants.
Few patients had remission after 24 weeks ac-
cording to the CDAI score, although the en-
rolled patients had relatively long durations of
rheumatoid arthritis and high CDAI scores at
baseline; the confidence interval comparing the
difference between olokizumab and adalimu­
mab for this end point included zero as well.
With either olokizumab dose or adalimumab,
approximately half the patients had low disease
activity (defined as a score of ≤10) on the CDAI
scale (Fig. S4), which is considered to be an
important treatment target in rheumatoid arthri-
tis by ACR, EULAR, and the Treat-to-Target Task
Force.2,27,28
An improvement of at least 70% in the ACR
response criteria (ACR70 response) was not in-
cluded in the ranked analysis schema to manage
n engl j med 387;8  nejm.org  August 25, 2022
multiple testing but was prespecified as an ex-
ploratory end point. Such a response occurred in
28% of the patients who received olokizumab as
compared with 11% who received placebo, but
no conclusions can be drawn from these results
(Table S10). In the placebo group, the percentage
of patients who had an ACR20 response or a
decrease in the HAQ-DI score was higher than
projected; however, these values were similar to
those observed in other trials.29,30
The trial was conducted in a relatively small
number of patients and over a short duration,
especially for the assessment of rare events or
events requiring longer durations of exposure
(e.g., cancers). With these limitations in mind,
serious infections were similar in frequency
among the active-treatment groups, occurring in
less than 2% of the patients in the two olokizu­
mab groups and in 3.5% of those in the adalimu­
mab group. Few cases of MACE were reported,
and such events were similarly distributed among
the groups. Anti–interleukin-6 receptor agents
are associated with elevations in levels of serum
lipids, alanine aminotransferase, and aspartate
aminotransferase to a greater extent than anti-
TNF drugs; these findings were seen in this
trial as well. A trial comparing cardiovascular
outcomes between an inhibitor of the interleu-
kin-6 receptor, tocilizumab, and TNF inhibition
showed no between-group difference in out-
comes.31,32 In our trial, overall drop-out rates for
safety events in the olokizumab groups were
similar to the rate in the adalimumab group. A
limitation of the trial was the lack of imaging
evaluation of joint disease.
In this phase 3 trial, treatment with olokizu­
mab plus methotrexate resulted in a higher
percentage of patients with an ACR20 response
over a 12-week period than placebo plus metho-
trexate, and olokizumab plus methotrexate was
noninferior to adalimumab plus methotrexate.
Longer and larger trials are required to deter-
mine the efficacy and safety of olokizumab in
patients with rheumatoid arthritis.
Presented in part at the annual meeting of the American Col-
lege of Rheumatology 2021 and the British Society for Rheuma-
tology Conference 2021.
Supported by R-Pharm.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank all the patients who participated in the trial, and
Sofia Kuzkina (R-Pharm) for medical writing assistance with an
earlier version of the manuscript.
725
 Olokizumab in Rheumatoid Arthritis
References
1. Aletaha D, Smolen JS. Diagnosis and
management of rheumatoid arthritis:
a  review. JAMA 2018;​320:​1360-72.
2. Fraenkel L, Bathon JM, England BR,
et al. 2021 American College of Rheuma-
tology guideline for the treatment of
rheumatoid arthritis. Arthritis Rheuma-
tol 2021;​73:​1108-23.
3. Smolen JS, Landewé RBM, Bijlsma
JWJ, et al. EULAR recommendations for
the management of rheumatoid arthritis
with synthetic and biological disease-
modifying antirheumatic drugs: 2019
update. Ann Rheum Dis 2020;​79:​685-99.
4. Clarke T. FDA declines to approve J&J
arthritis drug sirukumab. London:​Reuters,
September 22, 2017 (https://www​.­reuters​
.­com/​­article/​­us​-­johnson​-­johnson​-­arthritis/​
­fda​-­declines​-­t o​-­approve​-­jj​-­a rthritis​-­drug​
-­sirukumab​-­idUSKCN1BX2UY).
5. Takeuchi T, Thorne C, Karpouzas G,
et al. Sirukumab for rheumatoid arthritis:
the phase III SIRROUND-D study. Ann
Rheum Dis 2017;​76:​2001-8.
6. Aletaha D, Bingham CO III, Tanaka Y,
et al. Efficacy and safety of sirukumab
in patients with active rheumatoid ar-
thritis refractory to anti-TNF therapy
(SIRROUND-T): a randomised, double-
blind, placebo-controlled, parallel-group,
multinational, phase 3 study. Lancet 2017;​
389:​1206-17.
7. Taylor PC, Schiff MH, Wang Q, et al.
Efficacy and safety of monotherapy with
sirukumab compared with adalimumab
monotherapy in biologic-naïve pa-
tients with active rheumatoid arthritis
(SIRROUND-H): a randomised, double-
blind, parallel-group, multinational, 52-
week, phase 3 study. Ann Rheum Dis 2018;​
77:​658-66.
8. Weinblatt ME, Mease P, Mysler E, et al.
The efficacy and safety of subcutaneous
clazakizumab in patients with moderate-
to-severe rheumatoid arthritis and an in-
adequate response to methotrexate: re-
sults from a multinational, phase IIb,
randomized, double-blind, placebo/active-
controlled, dose-ranging study. Arthritis
Rheumatol 2015;​67:​2591-600.
9. Gabay C, Emery P, van Vollenhoven R,
et al. Tocilizumab monotherapy versus
adalimumab monotherapy for treatment
of rheumatoid arthritis (ADACTA): a ran-
domised, double-blind, controlled phase 4
trial. Lancet 2013;​381:​1541-50.
10. Burmester GR, Lin Y, Patel R, et al.
Efficacy and safety of sarilumab mono-
therapy versus adalimumab monotherapy
for the treatment of patients with active
rheumatoid arthritis (MONARCH): a ran-
domised, double-blind, parallel-group
phase III trial. Ann Rheum Dis 2017;​76:​
840-7.
726 n engl j med 387;8  nejm.org  August 25, 2022
11. Breedveld FC, Weisman MH, Kava­
naugh AF, et al. The PREMIER study:
a multicenter, randomized, double-blind
clinical trial of combination therapy with
adalimumab plus methotrexate versus
methotrexate alone or adalimumab alone
in patients with early, aggressive rheuma-
toid arthritis who had not had previous
methotrexate treatment. Arthritis Rheum
2006;​54:​26-37.
12. Kang S, Tanaka T, Narazaki M, Kishi-
moto T. Targeting interleukin-6 signaling
in clinic. Immunity 2019;​50:​1007-23.
13. Hunter CA, Jones SA. IL-6 as a key-
stone cytokine in health and disease. Nat
Immunol 2015;​16:​448-57.
14. Genovese MC, Fleischmann R, Furst
D, et al. Efficacy and safety of olokizumab
in patients with rheumatoid arthritis with
an inadequate response to TNF inhibitor
therapy: outcomes of a randomised phase
IIb study. Ann Rheum Dis 2014;​73:​1607-
15.
15. Takeuchi T, Tanaka Y, Yamanaka H,
et al. Efficacy and safety of olokizumab in
Asian patients with moderate-to-severe
rheumatoid arthritis, previously exposed
to anti-TNF therapy: results from a ran-
domized phase II trial. Mod Rheumatol
2016;​26:​15-23.
16. Nasonov E, Fatenejad S, Feist E, et al.
Olokizumab, a monoclonal antibody
against interleukin 6, in combination
with methotrexate in patients with rheu-
matoid arthritis inadequately controlled
by methotrexate: efficacy and safety re-
sults of a randomised controlled phase
III study. Ann Rheum Dis 2022;​81:​469-
79.
17. Aletaha D, Neogi T, Silman AJ, et al.
2010 Rheumatoid arthritis classification
criteria: an American College of Rheuma-
tology/European League Against Rheu-
matism collaborative initiative. Arthritis
Rheum 2010;​62:​2569-81.
18. Felson DT, Anderson JJ, Boers M, et al.
American College of Rheumatology pre-
liminary definition of improvement in
rheumatoid arthritis. Arthritis Rheum
1995;​38:​727-35.
19. Aletaha D, Smolen JS. The definition
and measurement of disease modification
in inf lammatory rheumatic diseases.
Rheum Dis Clin North Am 2006;​ 32:​
9-
44.
20. Keystone EC, Kavanaugh AF, Sharp
JT, et al. Radiographic, clinical, and func-
tional outcomes of treatment with adalimu­
mab (a human anti-tumor necrosis factor
monoclonal antibody) in patients with
active rheumatoid arthritis receiving con-
comitant methotrexate therapy: a random­
ized, placebo-controlled, 52-week trial.
Arthritis Rheum 2004;​50:​1400-11.
21. Weinblatt ME, Keystone EC, Furst DE,
et al. Adalimumab, a fully human anti-
tumor necrosis factor α monoclonal anti-
body, for the treatment of rheumatoid ar-
thritis in patients taking concomitant
methotrexate: the ARMADA trial. Arthri-
tis Rheum 2003;​48:​35-45.
22. Taylor PC, Keystone EC, van der
­Heijde D, et al. Baricitinib versus placebo
or adalimumab in rheumatoid arthritis.
N Engl J Med 2017;​376:​652-62.
23. Keystone EC, van der Heijde D, Kava-
naugh A, et al. Clinical, functional, and
radiographic benefits of longterm adalimu­
mab plus methotrexate: final 10-year data
in longstanding rheumatoid arthritis.
J Rheumatol 2013;​40:​1487-97.
24. Rubin DB. Multiple imputation for
nonresponse in surveys. Hoboken, NJ:​
John Wiley, 1987.
25. Felson DT, Smolen JS, Wells G, et al.
American College of Rheumatology/Euro-
pean League Against Rheumatism provi-
sional definition of remission in rheu-
matoid arthritis for clinical trials. Ann
Rheum Dis 2011;​70:​404-13.
26. Shaw S, Bourne T, Meier C, et al. Dis-
covery and characterization of olokizumab:
a humanized antibody targeting interleu-
kin-6 and neutralizing gp130-signaling.
MAbs 2014;​6:​774-82.
27. Smolen JS, Landewé R, Bijlsma J, et al.
EULAR recommendations for the man-
agement of rheumatoid arthritis with syn-
thetic and biological disease-modifying
antirheumatic drugs: 2016 update. Ann
Rheum Dis 2017;​76:​960-77.
28. Smolen JS, Breedveld FC, Burmester
GR, et al. Treating rheumatoid arthritis to
target: 2014 update of the recommenda-
tions of an international task force. Ann
Rheum Dis 2016;​75:​3-15.
29. Dougados M, van der Heijde D, Chen
Y-C, et al. Baricitinib in patients with in-
adequate response or intolerance to con-
ventional synthetic DMARDs: results from
the RA-BUILD study. Ann Rheum Dis
2017;​76:​88-95.
30. Combe B, Kivitz A, Tanaka Y, et al.
Filgotinib versus placebo or adalimumab
in patients with rheumatoid arthritis and
inadequate response to methotrexate:
a phase III randomised clinical trial. Ann
Rheum Dis 2021;​80:​848-58.
31. Ytterberg SR, Bhatt DL, Mikuls TR,
et al. Cardiovascular and cancer risk with
tofacitinib in rheumatoid arthritis. N Engl
J Med 2022;​386:​316-26.
32. Giles JT, Sattar N, Gabriel S, et al.
Cardiovascular safety of tocilizumab ver-
sus etanercept in rheumatoid arthritis:
a randomized controlled trial. Arthritis
Rheumatol 2020;​72:​31-40.
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