A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases
A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases
Angela Jin . Erhan Berber 0 1 2 3 4 5 6
0 D. E. Furst University of Washington , Seattle, WA , USA
1 D. E. Furst University of California, Los Angeles , Los Angeles, CA , USA
2 A. Rubbert-Roth (&) Kantonsspital St Gallen , St Gallen , Switzerland
3 Present Address: A. Rubbert-Roth Clinic for Rheumatology , Kantonsspital St. Gallen, St. Gallen , Switzerland
4 A. Jin E. Berber Genentech , South San Francisco, CA , USA
5 J. M. Nebesky F. Hoffmann-La Roche , Basel , Switzerland
6 D. E. Furst University of Florence , Florence , Italy
Tocilizumab (TCZ) is the first humanized antiinterleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced
cytokine release syndrome. The global clinical
development program for TCZ provides a
wealth of clinical data on intravenous TCZ, and
more recent studies in patients with RA have
provided evidence characterizing the role of
intravenous TCZ as monotherapy in early
disease and led to the introduction of a
subcutaneous formulation of TCZ. In addition, recently
published open-label extension and
observational studies continue to support the
longterm efficacy and safety of TCZ in both clinical
trial and real-world settings. Given the
involvement of IL-6-mediated signaling in
inflammatory disorders, TCZ is also being
investigated in other immunological diseases.
In particular, a phase 2 trial on the safety and
efficacy of subcutaneous TCZ in adults with
systemic sclerosis shows clinically relevant
improvements in skin sclerosis and lung
function in these patients. Another anti-IL-6
receptor agent, sarilumab, targeting the IL6 receptor
alpha subunit, was recently approved for the
treatment of patients with RA, although
longterm data for this biologic are not yet published.
In this article we review the placement of TCZ
in current treatment guidelines; recent clinical
trial data, including quality of life in patients
with RA; recent updates to the TCZ safety
profile; recent investigations of TCZ in other
immunological diseases; and the clinical
development of other novel IL-6-targeted agents.
TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTORNEUTRALIZING BIOLOGIC
Interleukin-6 (IL-6) is a multifunctional
cytokine that plays an important role in both acute
and chronic inflammatory responses.
Consequently, the dysregulated or persistent
production of IL-6 can lead to the development of
inflammatory disorders [
]. Elevated levels of
IL6 in serum, synovial fluid, and various tissues
have been correlated with disease activity in
patients with rheumatoid arthritis (RA) [
juvenile idiopathic arthritis (JIA) [
Castleman’s disease [
], systemic sclerosis (SSc) [
giant cell arteritis (GCA) [
Still’s disease (AOSD) , familial
Mediterranean fever (FMF) [
], polychondritis [
]. These associations suggest a
pathogenetic role for IL-6 in multiple
inflammatory conditions and form the basis of the
rationale for the development of anti-IL-6
Tocilizumab (TCZ) is the first humanized
monoclonal antibody targeting the IL-6
receptor subunit alpha (IL-6Ra) [
], and its
mechanism of action has been described in detail in
previous reviews [
]. Briefly, TCZ targets
both membrane-bound and soluble IL-6Ra,
which prevents the binding of IL-6 to both the
IL-6R and the signal transducer glycoprotein
130 complex and results in turn in inhibition of
the downstream classic signaling and
trans-signaling cascades involving the Janus-activated
kinase-signal transducer and activator of
transcription (JAK-STAT) pathway (Fig. 1) [
Through this mechanism, TCZ decreases the
circulating levels of neutrophils, neutrophil
infiltration into inflamed joints [
of myeloid dendritic cells [
], monocyte levels,
serum macrophage migration inhibitory factor
], and levels of T helper 17 (Th17)
cells, while increasing regulatory T cells [
TCZ also induces regulatory B-cell expansion,
decreases B-cell hyperactivity, and decreases the
number of peripheral memory B cells.
Immunogenicity to TCZ (antidrug antibodies) is
In this review we briefly summarize the
clinical development that supports the approval
of TCZ by regulatory authorities for the
treatment of Castleman’s disease, JIA, and RA that
has been reviewed previously. A more detailed
review is provided of the placement of TCZ in
recent RA treatment guidelines; recent TCZ
clinical trial data, including quality of life
(QOL) in patients with RA; recent updates to the
TCZ safety profile; investigations in recently
approved and nonapproved immunological
diseases; and the clinical development of novel
This article is based on previously conducted
studies and does not involve any new studies of
human or animal subjects performed by any of
TCZ: BRIEF OVERVIEW OF DEVELOPMENT FOR USE IN APPROVED INDICATIONS
The key trials that contributed to the global
clinical development of TCZ for use in its
approved indications—RA, Castleman’s disease,
systemic JIA (sJIA), polyarticular JIA (pJIA), and
GCA—are shown in Fig. 2.
In 2005, TCZ was initially approved for the
treatment of Castleman’s disease in Japan,
where it significantly alleviated chronic
inflammatory symptoms and wasting and
demonstrated good tolerability [
Juvenile Idiopathic Arthritis
The results of Japanese phase 3 trials
demonstrated that TCZ effectively treated children
with systemic and pediatric JIA (sJIA and PJIA,
respectively), as measured by JIA American
College of Rheumatology (ACR) response rates.
This resulted in its approval for both indications
Fig. 1 Interleukin-6 (IL-6) signaling. IL-6 binds to and
forms a complex with the IL-6 receptor and glycoprotein
130 (gp130), resulting in the homodimerization of gp130
and subsequent activation of the signaling system via classic
signaling or trans-signaling pathways. The humanized
IL-6 receptor monoclonal antibody tocilizumab targets
both soluble and membrane-bound IL-6 receptors, thus
inhibiting the binding of IL-6 to both receptors. JAK
Janus-activated kinase, MAPKs mitogen-activated protein
kinases, SHP-2 Src-homology 2 domain-containing
protein tyrosine phosphatase, STAT signal transducer and
activator of transcription. Reproduced with permission
from Tanaka et al. [
]. Copyright Cold Spring Harbor
in Japan in 2008 [
]. In 2011, TCZ was
approved in the USA and the European Union
(EU) for the treatment of sJIA, and in 2013, for
the treatment of pcJIA based largely on phase 3
data from the TENDER and CHERISH trials, in
which the signs and symptoms of sJIA and
pcJIA, respectively, were improved in children
treated with TCZ compared to placebo [
Giant Cell Arteritis
Tocilizumab was approved for the treatment of
patients with GCA, a vasculitis of medium- and
large-sized arteries, by the U.S. Food and Drug
Administration (FDA) on 22 May 2017 and by
the European Commission on 22 September
2017, making this the first drug approved for
the treatment GCA beyond glucocorticoids,
which are associated with substantial morbidity
from glucocorticoid-related complications
following prolonged use [
Analysis of biopsy specimens from patients
with GCA using quantitative real-time PCR
identified proinflammatory pathogenic
pathways mediated by Th17, which promotes the
release of IL-1b, IL-6, and IL-23 cytokines, and
of Th1, which promotes the release of IL-12
cytokines; these cells contribute to the systemic
and vascular manifestations of GCA [
]. As a
result, biologic therapies targeting these
proinflammatory pathways are logical targets for the
treatment of GCA.
The published results of a randomized
double-blind phase 2 trial of TCZ in patients with
GCA were the first to demonstrate the
induction and maintenance of remission in a clinical
trial setting [
]. Compared to the placebo
group, the TCZ group had higher rates of
complete remission at week 12 (85 vs. 40%) and
higher relapse-free survival at week 52 (85 vs.
extension, MTX methotrexate, OL open-label, pJIA
polyarticular juvenile idiopathic arthritis, RA rheumatoid
arthritis, SC subcutaneous, sJIA systemic juvenile
idiopathic arthritis,TNFi tumor necrosis factor inhibitor, US
United States of America
Recently, a randomized, double-blind,
placebo-controlled, multicenter, phase 3 trial
(GiACTA) of TCZ in patients with GCA showed
that TCZ ? a 26-week prednisone taper was
superior to both 26-week and 52-week
prednisone tapers alone for the achievement of
sustained remission from GCA [
remission at 12 months was achieved by 56% of
patients receiving weekly TCZ ? 26-week
prednisone taper and 53.1% of those receiving
every-other-week TCZ ? 26-week prednisone
taper, compared with 14% of patients receiving
the 26-week prednisone taper alone (P\0.0001
for both comparisons). Both TCZ groups were
also superior to the 52-week prednisone taper
alone group in terms of sustained remission
from GCA (P B 0.0002). The addition of TCZ to
prednisone treatment in the GiACTA trial also
allowed a reduction in the cumulative
prednisone doses required for disease control, with a
median cumulative steroid exposure of 1862.0
mg in both TCZ groups compared with 3817.5
mg in the 52-week prednisone taper group and
3296.0 mg in the 26-week prednisone taper
]. Kaplan–Meier analysis of data from
GiACTA demonstrated that patients with
higher TCZ exposure (i.e., those receiving
weekly TCZ) experienced a longer time to first
flare of GCA [
In summary, TCZ is now approved for the
treatment of GCA, and the findings of the
GiACTA trial indicate that early initiation of
TCZ therapy in patients with GCA allows the
reduction of glucocorticoid use and cumulative
glucocorticoid dose and achieves a reduced flare
Chimeric Antigen Receptor T-Cell
Therapy-Induced Cytokine Release
In August 2017, TCZ was approved by the FDA
for the treatment of chimeric antigen receptor
(CAR) T-cell therapy-induced cytokine release
]. This approval was based on
retrospective analysis of pooled data from
clinical trials of CAR T-cell therapies for blood
Early Clinical Development in RA
The initial clinical development of TCZ for the
treatment of RA has been reviewed previously
]. Five randomized, double-blind, controlled,
multicenter, phase 3, pivotal clinical trials were
central to the approval of TCZ by regulatory
authorities of TCZ in the EU and the USA for the
treatment of RA (Fig. 2) [
] and TOWARD [
showed that treatment with TCZ at 4 and 8 mg/
kg body weight in combination with
methotrexate (MTX) or other conventional
synthetic disease-modifying antirheumatic
drugs (csDMARDs) reduced the signs and
symptoms of RA in patients who responded
inadequately to MTX/csDMARDs alone. The
LITHE trial [
] demonstrated a greater
inhibition of structural joint damage and greater
improvement in physical function with TCZ 4
and 8 mg/kg ? MTX than with MTX alone in
patients with RA who were inadequate
responders to MTX alone. The RADIATE trial [
showed that TCZ prescribed at 4 and 8 mg/kg
reduced the signs and symptoms of RA in
patients who responded inadequately to
treatment with tumor necrosis factor (TNF)
inhibitors. The AMBITION trial [
] showed that
montherapy with TCZ at 8 mg/kg was superior
to monotherapy with MTX in terms of
improving signs and symptoms of RA in
patients for whom previous treatment with
MTX or biologics had not failed.
Dosing and Dose–Response in RA
The recommended initial dosing regimen for
TCZ in patients with RA differs between the EU
and the USA. A starting dosage of TCZ 8 mg/kg
every 4 weeks is recommended in the EU [
whereas a starting dosage of 4 mg/kg every
4 weeks is recommended in the USA, with the
option of increasing to 8 mg/kg based on
clinical response and at the treating physician’s
The five pivotal phase 3 studies of TCZ
suggested a possible dose response for TCZ 4 and
8 mg/kg; however, the studies were not powered
to detect differences between the two dosing
]. Numerical differences in
efficacy outcomes were evident between dosing
at TCZ 4 and 8-mg/kg, suggesting that some
patients may respond well to TCZ 4 mg/kg.
Real-world data show that a large proportion
of patients in the USA increase their TCZ dosage
from 4 to 8 mg/kg soon after initiating
treatment. Analysis of data from patients with RA in
the comparative-effectiveness CERTAIN
substudy nested within the U.S. Corrona Registry
revealed patterns of TCZ dose escalation in a
real-world setting [
]. Among the patients with
RA who initiated TCZ treatment and completed
the visits at the predetermined 3- and 6-month
time points in this substudy (N = 213), 86
(40.4%) remained on the initial dosage of 4 mg/
kg and 110 (51.6%) increased their dosage to
8 mg/kg by 3 months [
]. Improvements in
measures of disease activity and moderate or
good European League Against Rheumatism
(EULAR) response rates were also observed at 3
and 6 months in both groups, suggesting that
flexibility in dosing may be possible [
Although the sample size of the Corrona
analysis was small, the results are consistent with
those from an analysis of U.S. healthcare claims
data that included 3600 patients with RA who
received TCZ intravenously between January
2016 and April 2017. During this period, 31% of
patients received TCZ 4 mg/kg, 42% received
TCZ 8 mg/kg, and 27% switched between the
two dosing regimens over the course of the
observation period (83% switched from 4 to
8 mg/kg). Furthermore, data between May 2016
and April 2017 indicated stable dosing patterns
over 12 months, with approximately 64% of
patients receiving TCZ 8 mg/kg (Symphony
Health Source Healthcare Analytics claims,
unpublished data). Subcutaneous (SC)
administration of TCZ was received weekly in 66% of
patients and biweekly in 34% of patients
between January 2016 and April 2017
(Symphony Health Source Healthcare Analytics
claims, unpublished data). Although the sample
size and methodology for this U.S. claims data
analysis differed from that of the Corrona
analysis, both analyses indicated that a
substantial proportion of patients switched from
TCZ 4 mg/kg to TCZ 8 mg/kg.
In summary, there is some indication of a
dose–response relationship with TCZ, but this
does not apply to all patient populations. It is
the authors’ impression that based on
numerical trends, there will be some patients who
respond well to the 4 mg/kg dosing regimen.
Although data are sparse, some patients may be
able to decrease their dosage from 8 to 4 mg/kg
after a period of disease control.
Update on QOL and Patient-Reported
Outcomes in RA
A systematic literature review of randomized
controlled trials of TCZ in patients with RA
reported improved physical function and QOL
]. TCZ was associated with greater
improvements in disease-related function (as measured
by the Health Assessment Questionnaire
Disability Index [HAQ-DI]) and QOL (measured
with the 36-Item Short Form Health Survey
[SF36]) compared with control treatments
(placebo, MTX, or csDMARDs); the odds ratio for
improvement in HAQ-DI was 1.4 for controls
versus 7.0 in favor of TCZ [
exceeding minimal clinically important
differences (MCIDs) were reported for the SF-36
Physical Component Summary (PCS;
MCID 5.0), SF-36 Mental Component Summary
(MCS; MCID 5.0), and Functional Assessment of
Chronic Illness Therapy (FACIT) Fatigue Scale
scores (MCID 4.0) [
Taken together, data from eight phase 3 or 4
trials also support clinically relevant
improvements in HAQ-DI scores (MCID [ 0.5). Results
from the TCZ treatment groups in these trials
were generally statistically significantly better
than those in the comparator groups, although
improvements in HAQ-DI scores were often
observed in the comparator groups as well
]. For example, the ADACTA trial
comparing TCZ monotherapy to adalimumab
monotherapy demonstrated mean HAQ-DI
score improvements of - 0.7 for TCZ and - 0.5
for adalimumab (difference in adjusted means:
- 0.2; 95% confidence interval [CI] - 0.3 to 0.0;
P = 0.0653). A higher proportion of TCZ-treated
patients than adalimumab-treated patients
reported improvement in HAQ-DI scores of at
least a MCID of 0.22 (92/163 [56.4%] vs. 83/162
[51.2%], respectively), although there was no
statistically significant difference .
Altogether, improvements in QOL were observed in
patients who were MTX naive [
inadequate responders (or with
contraindication or intolerance to MTX) [
48, 49, 53
csDMARD inadequate responders [
TNF inhibitor inadequate responders [
duration of response reported varied from 24 to
104 weeks, which is in line with the duration of
each trial [
], except for one trial in
which improvement in HAQ-DI scores was
observed at week 24, but not at weeks 52 or 104
Changes in the SF-36 PCS and MCS scores
have been reported in two phase 3 trials and in a
post hoc analysis of the RADIATE trial
49, 51, 55
]. The ADACTA trial reported
improvements in SF-36 PCS scores of 9.2 for
TCZ 8 mg/kg and 7.6 for adalimumab (both
greater than the MCID but not statistically
significantly different between treatment groups;
P = 0.1641); SF-36 MCS scores were 7.9 and 5.0,
respectively (P = 0.0497) [
]. Similar results
were reported for both the FUNCTION and
RADIATE trials [
Improvements in fatigue, as assessed by the
FACIT Fatigue Scale, were observed for both
TCZ and adalimumab in the ADACTA trial
(adjusted mean change to week 24 was 11.4 for
TCZ and 8.9 for adalimumab; difference: 2.5;
95% CI - 0.3 to 5.3; P = 0.0770) [
] and for
TCZ in a post hoc analysis of the RADIATE trial
(mean changes to week 24 were 6.66 for TCZ
4 mg/kg and 8.83 for TCZ 8 mg/kg) [
In summary, the results of randomized
controlled clinical trials show that TCZ improves
health-related activities of daily living and other
aspects of QOL, such as the domains of the
SF36 and the FACIT Fatigue Scale. Although
patient-reported outcome studies are often
uncontrolled and subject to problems of
selection and outcome bias, they provide important
supportive data suggesting that TCZ is
associated with improving these outcomes.
TCZ: RECENT DEVELOPMENTS IN RA
The recent development of TCZ use in the RA
setting includes evidence further characterizing
its use as monotherapy and in patients with
early RA, as well as the introduction of an SC
formulation of TCZ (TCZ-SC). Furthermore,
recently published open-label extension (OLE)
and observational studies inform the long-term
efficacy and safety of TCZ beyond 2 years.
TCZ as Monotherapy
Two randomized, double-blind, controlled
clinical trials assessed TCZ as monotherapy in
patients with active RA despite an inadequate
response to MTX (ACT-RAY) [
separately, in patients with severe RA who were
intolerant to or inappropriate for continued
MTX treatment (ADACTA) [
The phase 3 ACT-RAY trial demonstrated
that there were no clinically relevant differences
between adding TCZ 8 mg/kg to the MTX
therapeutic regimen (mean disease duration at
baseline 8.2 years) and switching to
monotherapy with TCZ 8 mg/kg (mean disease duration
at baseline: 8.3 years) after 24 weeks of therapy
when disease activity was measured using the
Disease Activity Score based on 28 joints
(DAS28) and erythrocyte sedimentation rate
(ESR) remission (DAS28-ESR\2.6; 40.4% in the
add-on group vs. 34.8% in the monotherapy
group). There were also no relevant differences
in the assessments of radiographic progression
of structural damage (Genant-modified Sharp
score progression of the smallest
detectable change or less: 91 vs. 87%) [
These efficacy measures were maintained at
week 52 for both DAS28-ESR-defined remission
(45.5 vs. 36.6% and p = 0.03) and radiographic
progression (92.8 vs. 86.1% of patients) [
In the phase 4 ADACTA trial, monotherapy
with TCZ 8 mg/kg (mean disease duration at
baseline 7.3 years) was superior to monotherapy
with the TNF inhibitor adalimumab 40 mg
every 2 weeks (mean disease duration at
baseline 6.3 years) in incomplete responders to MTX
(inadequate response, contraindication, or
intolerance to MTX). Reductions from baseline
in the DAS28-ESR were significantly greater
with TCZ than adalimumab (- 3.3 vs. - 1.8;
The FUNCTION trial in MTX-naive patients
with early RA (mean disease duration at baseline
0.4–0.5 years) [
] and the SURPRISE trial in
patients with inadequate response to MTX
(mean disease duration at baseline
3.6–3.8 years) [
] included TCZ ? MTX
combination therapy and TCZ monotherapy treatment
arms. Although the FUNCTION trial was not
powered for comparisons between TCZ
combination therapy and TCZ monotherapy, the TCZ
8 mg/kg ? MTX group consistently achieved
the best outcomes for all efficacy measures,
including DAS28-defined remission [
SURPRISE trial reported higher rates of
DAS28defined remission in patients who added TCZ to
their MTX treatment regimen compared with
those who switched from MTX to TCZ at week
24 (primary end point), but the DAS28-defined
remission rates were not significantly different
at week 52 or for other efficacy end points, and
there was no significant difference in rates of
structural remission or clinically relevant
radiographic progression (change in the
modified total Sharp score [mTSS] C 3) between the
add-on and the switch groups. However, among
seven add-on and 15 switch patients who did
experience clinically relevant radiographic
progression, the mean change in total mTSS was
greater in the switch group than in the add-on
group (9.0 vs. 5.0/year; P = 0.04), suggesting
that adding TCZ to MTX monotherapy may
lead to superior clinical efficacy and prevent
joint destruction compared with switching
from MTX to TCZ monotherapy [
In summary, in patients with disease
duration ranging between 6.7 and 8.3 years,
monotherapy with the intravenous formulation
of TCZ (TCZ-IV) at 8 mg/kg seems to be as
effective as adding TCZ to MTX monotherapy
(combined TCZ ? MTX therapy) for incomplete
responders to MTX monotherapy. TCZ added to
MTX may provide some benefit over TCZ
monotherapy in patients with shorter disease
duration, but this therapeutic option needs
SC Formulation of TCZ
Two randomized, double-blind, comparative,
phase 3 studies demonstrated the noninferiority
of TCZ-SC to TCZ-IV according to standard
outcome measures/response rates of the ACR for
20% improvement (ACR20) at week 24 in
patients with RA and an inadequate response to
csDMARDS and/or biologic DMARDS
(bDMARDs; MUSASHI trial) [
] or to only
csDMARDs (SUMMACTA trial) [
]. In addition,
similar rates of ACR50 (50% improvement) and
ACR70 (70% improvement) responses between
TCZ-SC and TCZ-IV were reported [
An 84-week OLE of the MUSASHI trial
demonstrated maintenance of efficacy for
DAS28-ESR-defined remission rates between
patients continuing TCZ-SC treatment and
those switching from TCZ-IV to TCZ-SC [
The long-term efficacy and safety of TCZ-SC was
also maintained through 97 weeks and found to
be comparable to that of TCZ-IV in a 72-week
OLE of the SUMMACTA study [
]. TCZ-SC is
approved in Japan, the USA (2013), and the EU
(2014) for adult patients with RA [
The single-arm, open-label, multinational,
phase 4 TOZURA trial is currently evaluating
the efficacy and safety of 24 weeks of treatment
with weekly TCZ-SC 162 mg as either
monotherapy or in combination with a
csDMARD (at the investigator’s discretion) in
patients with RA who had an inadequate
response to bDMARDs or csDMARDs [
interim analysis of 1246 patients demonstrated
equivalent DAS28-ESR and Clinical Disease
Activity Index remission rates for both TCZ
monotherapy and combination therapy at week
24. These interim results are promising and
completed results are anticipated.
In summary, TCZ-SC appears to be as
effective as TCZ-IV with comparable safety
(discussed below in section Safety,
Pharmacokinetics, and Immunogenicity).
TCZ in Early RA
Two randomized, double-blind, multicenter,
phase 3 trials have studied TCZ in MTX-naive
patients with early (B 2 years) progressive RA
(FUNCTION trial) [
] and in DMARD-naive
patients (U-ACT-Early study) [
]. The 2-year
U-ACT-Early study demonstrated that more
patients treated with TCZ 8 mg/kg
monotherapy and TCZ 8 mg/kg ? MTX combination
therapy achieved sustained remission and low
disease activity (DAS28-ESR\2.6 with swollen
joint count B 4, persisting for C 24 weeks) than
those treated with MTX alone (84 and 86% vs.
44%, respectively; both P\0.0001), with no
significant differences between TCZ
monotherapy versus combined TCZ ? MTX therapy [
In the FUNCTION trial, patients treated with
TCZ 8 mg/kg monotherapy and TCZ 8 mg/kg ?
MTX achieved significantly higher rates of
DAS28-ESR-defined remission at week 24 than
those treated with MTX monotherapy (44.8 and
38.7% vs. 15%, respectively; P\0.0001), with
similar clinical efficacy observed between TCZ
monotherapy and the combination therapy
]. The difference in remission rates between
these two studies may possibly be ascribed to
approximately 20% of the FUNCTION study
population having previously received one or
more csDMARD [
], whereas patients enrolled
in the U-ACT-Early trial were csDMARD-naive
In summary, in patients with\2 years of
disease duration, these two studies demonstrate
that TCZ 8 mg/kg monotherapy or combined
TCZ 8 mg/kg ? MTX therapy improved
DAS28ESR-defined remission rates compared to MTX
monotherapy and that adding MTX to TCZ
therapy did not improve TCZ response. In 2014,
TCZ received approval in the EU for use in early
RA (i.e., severe, active, and progressive RA not
previously treated with MTX) [
Long-Term OLE and Observational Studies
Although several OLE and observational studies
of\2 years’ duration have been conducted, this
section focuses on those with a study
duration[2 years to provide more clinically
Inhibition of radiographic progression was
maintained through 5 years in a 3-year OLE
study of the LITHE trial, with less radiographic
progression observed for patients originally
randomly assigned to receive TCZ than for
those originally assigned to receive placebo
(Genant-modified TSS 1.34 and 3.02,
The long-term clinical efficacy of TCZ
monotherapy in patients with RA who were
MTX- or biologic-naive was also assessed in an
OLE of the AMBITION trial, which reported
sustained improvements in DAS28-ESR-defined
remission and ACR response rates through
264 weeks of follow-up in patients remaining
on their study medication [
]. A multicenter
prospective observational cohort study
evaluating clinical responses and radiographic end
points for TCZ during 3 years of treatment in
Japanese patients with RA reported sustained
(C 6 months) reductions in DAS28-ESR scores,
along with improvements in both clinical
(Boolean remission) and structural
(Genantmodified TSS) remission rates during 3 years of
In summary, these studies support the
longterm efficacy of TCZ-IV in patients remaining
on TCZ treatment, in both clinical trial
followup studies and real-world observational cohorts.
A long-term decrease in the rate of radiographic
progression is also demonstrated.
SAFETY, PHARMACOKINETICS, AND IMMUNOGENICITY
The safety of TCZ-IV and TCZ-SC has been
reported in 11 published phase 3 and 4 trials
40, 42–44, 49–52, 56, 59, 65
]. The most
common adverse events (AEs) and serious AEs (SAEs)
reported in patients with RA treated with TCZ in
these trials were infections, such as
nasopharyngitis, upper respiratory tract
infections, pneumonia, and cellulitis. Other SAEs of
interest reported in patients with RA treated
with TCZ include gastrointestinal perforations
(GIPs), malignancy, myocardial infarction, and
stroke. Abnormalities in laboratory test results
have also been reported, including elevated
liver enzyme levels, decreased neutrophil
counts, and changes in lipid levels. Other safety
signals were not identified in a cumulative
analysis of up to 4.6 years of TCZ exposure
based on pooled data from the OPTION,
TOWARD, RADIATE, AMBITION, and LITHE
phase 3 trials (with 12,293 patient-years of
exposure) compared with the
placebo-controlled periods; infections were the most
common AEs and SAEs [
]. As of 7 June 2017, the
estimated cumulative TCZ exposure in the
periodic benefit–risk evaluation report is
[700,000 patient-years (F. Hoffmann–La Roche
Ltd., data on file).
A higher incidence of GIPs and specifically
lower intestinal perforations (LIPs) has been
reported in patients treated with TCZ than in
those treated with other biologics or csDMARDs
(rates per 1000 patient-years: GIPs, 1.8–2.8 for
TCZ vs. 0.6–0.9 for TNF inhibitors
[difference: 1.2 - 1.9/1000 patient-years]; LIPs,
1.26–2.7 for TCZ vs. 0.2–0.76 for TNF inhibitors)
]. For every 1000 patients treated with
TCZ per year, between one and two additional
GIPs might be expected to occur for patients
treated with TCZ compared with those treated
with TNF inhibitors [
]. In particular, the risk
for LIPs seems to be higher in patients with a
history of diverticulitis [
], indicating that
TCZ should be avoided in patients at risk for
GIP. Furthermore, TCZ-treated patients with LIP
often exhibit only mild or no symptoms and
suppressed C-reactive protein (CRP) levels,
which may delay diagnosis . These findings
indicate a class effect for anti-IL-6 agents,
highlighting the need for careful patient
selection (i.e., exclusion of individuals with
previous diverticulitis) in clinical trials evaluating
TCZ and other anti-IL-6 agents in order to
reduce the risk for LIP.
Neutropenia and malignancy are two
additional safety issues of interest for patients
receiving TCZ. In a retrospective cohort study of
patients with rheumatic diseases, TCZ was
associated with a higher incidence of
neutropenia compared with abatacept and
infliximab (18.6% vs. 3.8% and 2.8%, respectively;
P\0.001). This increased incidence of
neutropenia did not result in a higher risk for severe
]. Despite concerns for the risk for
malignancy during immunosuppressive therapy
in patients with RA, an analysis of phase 3 trials
and long-term extension studies did not
demonstrate increased risk for overall or
sitespecific malignancies above the risk expected in
(BW < 30 kg)
every 4 weeks
(BW ‡ 30 kg)
every 4 weeks
Volume of distribution (L)
4 mg/kg 8 mg/kg
every 4 every 4
AUC Area under the concentration curve, BW body weight, Cmax maximum concentration, Cmin minimum concentration,
IV intravenous, NA not available, pJIA polyarticular juvenile idiopathic arthritis, PK pharmacokinetics, SC subcutaneous,
SD standard deviation, sJIA systemic juvenile idiopathic arthritis, t1/2 half-life, TCZ tocilizumab
patients with RA [
]. However, patients treated
with TCZ should be monitored for malignancies
to provide data that can be used for to assess risk
over the longer term.
The data for the pharmacokinetics (PK) of
TCZ-IV and TCZ-SC are based on population PK
analyses of 1793 and 1759 patients with RA,
]. In addition, population PK
analyses of 75 patients with sJIA and 188
patients with pJIA have been conducted to
determine the PK of TCZ-IV in these patients (F.
Hoffmann–La Roche Ltd., data on file). We have
summarized the PK profiles in Table 1
37, 72, 73
]. PK exposure parameters for TCZ
were found to be similar between healthy
individuals and patients with RA, indicating that
even the presence of active disease does not
impact the PK profile of TCZ [
]. The PK profile
of TCZ is not affected by alcohol, age, or
ethnicity. In addition, no clinically relevant
additive effects on the PK profiles of TCZ and MTX
were observed when they were administered
together in patients with RA [
]. This result
was also supported by the FUNCTION trial,
which reported similar serum TCZ levels in
patients receiving or not receiving MTX in
combination with TCZ .
Clinical experience with both TCZ-IV and
TCZ-SC has demonstrated low immunogenicity
in several indications, including RA [
Castleman’s disease [
], and JIA [
28, 29, 31
a pooled analysis of data from 13 phase 3
clinical trials (8 TCZ-IV, 5 TCZ-SC) and one TCZ-IV
safety study, antidrug antibodies were identified
in 47 of 3094 (1.5%) and 69 of 5806 (1.2%)
patients treated with TCZ-SC and TCZ-IV,
]; neutralizing antidrug
antibodies were confirmed in 40 of 3094 (1.3%) and
54 of 5806 (0.9%) of these patients, respectively
In summary, the safety, PK, and
immunogenicity of TCZ-SC appear to be similar to those
THE ROLE OF TCZ IN CURRENT TREATMENT REGIMENS FOR RA
Tocilizumab has been incorporated as a
treatment option into current ACR and EULAR
recommendations for the management of RA
]. ACR 2015 guidelines recommend that
a non-TNF biologic (rituximab or TCZ), with or
without MTX, can be considered if disease
activity remains moderate or high despite the
use of csDMARDs or after failure of TNF
inhibitor treatment . EULAR 2016 updated
guidelines recommend TCZ as a bDMARD
]. A treatment target of sustained
remission or low disease activity is
recommended in the guidelines for every patient, with
the goal of achieving sustained remission. For
patients who do not improve or reach their
target end point after receiving csDMARDs for
3–6 months, a bDMARD or a targeted synthetic
DMARD (tsDMARD), such as tofacitinib or
baricitinib, should be added to the treatment
regimen. The guidelines state that bDMARDs
should usually be initiated in combination with
a csDMARD except in patients who cannot use
them as comedication, in which case IL-6
pathway inhibitors and tsDMARDs may offer
some advantages over other bDMARDs.
In summary, updated guidelines regarding
csDMARDs, bDMARDs, and tsDMARDs include
the use of non-TNF-inhibitor biologics, such as
TCZ (abatacept or rituximab) and place these
drugs in the RA armamentarium. However, the
specific position of TCZ in the treatment
algorithm is yet to be determined.
TCZ: PROMISING RESEARCH, INCLUDING POTENTIAL INDICATIONS
Given that IL-6 is involved in both innate and
adaptive immune responses, inhibition of
IL-6mediated signaling with TCZ may be an
effective therapeutic approach for the treatment of
SSc. Initial clinical experience with TCZ in SSc
includes softening of the skin and histological
thinning of the collagen fiber bundles in the
dermis of two patients with SSc [
], while a
small observational study of patients with SSc
and refractory polyarthritis reported the
achievement of a good EULAR response in 10 of
15 patients [
]. In the recent double-blind
phase 2 faSScinate trial, there was encouraging
(although not statistically significant)
numerical improvement in skin thickening and
evidence of less decline in lung function in adult
patients with progressive SSc treated with
TCZSC compared to those receiving placebo [
Further studies are needed, and an ongoing
2-year randomized phase 3 trial of TCZ-SC
162 mg in SSc is under way (ClinicalTrials.gov
Steroid Sparing in RA
A trial assessing the steroid-sparing ability of
TCZ (SEMIRA trial; ClinicalTrials.gov identifier
NCT02573012) is currently in progress. The aim
of this study is to evaluate the efficacy of
maintenance treatment with TCZ-SC or TCZ-IV
with or without stable doses of csDMARD in
patients with RA who have DAS-defined low
disease activity (B 3.2) for C 4 weeks before
randomization and have been receiving
glucocorticoids (5–15 mg/day of prednisone or
equivalent) for C 20 weeks before screening.
Eligible patients were randomly assigned to
receive either a blinded 24-week prednisone
tapering regimen or a blinded continuation of
prednisone 5 mg/day for 24 weeks. Patient
recruitment for the SEMIRA trial is now
completed and the results are pending.
Given the far-reaching involvement of
IL-6mediated signaling in inflammatory disorders,
TCZ is being investigated in a number of other
The TENOR trial was a prospective,
open-label, longitudinal, multicenter study evaluating
TCZ therapy in patients with polymyalgia
rheumatica (PMR); significant reductions in
18Ffluorodeoxyglucose (18F-FDG) uptake (assessed
by positron emission tomography-computed
tomography) following TCZ therapy suggested a
decrease in disease activity [
the randomized, double-blind,
placebo-controlled, phase 3 SEMAPHORE trial is recruiting
patients and will evaluate the safety and efficacy
of TCZ in patients with PMR who are
glucocorticoid dependent (ClinicalTrials.gov
A small multicenter study of 11 patients with
uveitis associated with Behc¸et’s disease reported
improvements in visual acuity, number of
blood cells in the anterior chamber of the eye,
vitritis, retinal vasculitis, optical coherence
tomography, achievement of complete
remission, and prednisone dose reduction in patients
receiving TCZ therapy [
]. Early-phase trials
are under way to evaluate both TCZ-IV
(ClinicalTrials.gov identifier NCT01717170) and
TCZSC (ClinicalTrials.gov identifier NCT02929251)
in patients with noninfectious uveitis.
No published prospective clinical trials
evaluating TCZ in AOSD are available, but
promising efficacy results have been observed in
several case reports and retrospective analyses
]. Improvements in clinical (fever, rash,
and myalgia) and laboratory (ESR and CRP)
manifestations were observed after treatment
with TCZ in a review of 24 cases of AOSD in
Korean patients . A multicenter study of 75
patients with AOSD treated with TCZ or
anakinra also reported similar improvements in
clinical manifestations (fever, articular, rash,
and lymphadenopathy) over 12 months of
therapy between the two study treatments,
although improvements in CRP and ESR levels
appeared to be greater with TCZ than with
]. Furthermore, the preliminary
results of a small, prospective, single-arm pilot
study in eight patients recently reported no
significant AEs with TCZ monotherapy and
improvement rates of 100% for fever, 75.0% for
arthralgia, and 71.4% for eruption at 6 months
in patients with AOSD [
Evidence from case reports, small studies,
and retrospective studies suggest that TCZ may
be an effective therapeutic option in vasculitis
syndromes other than GCA, including systemic
rheumatoid vasculitis, PMR, Takayasu arteritis,
and Behc¸et’s disease [
]. TCZ has also
shown promise in several other indications,
including amyloidosis [
], FMF [
Schnitzler’s syndrome [
]. Results of the
doubleblind, randomized, placebo-controlled, phase 3
TAKT trial in 36 patients with Takayasu arteritis
demonstrated a trend toward relapse
suppression in favor of TCZ-SC over placebo [
However, the primary end point (time to first
protocol-defined relapse) was not met in the
intent-to-treat population (hazard ratio = 0.41;
95.41% CI 0.15–1.10; P = 0.0596). TCZ-SC
showed numerically favorable (though not
statistically significant) trends for improvement in
objective systemic symptoms, subjective
systemic symptoms, elevated inflammation marker
levels, vascular lesions, and ischemic symptoms
accompanied by organ lesions in the TAKT trial
]. TCZ was approved in August 2017 for the
treatment of Takayasu arteritis in Japan based
on the results of the TAKT study.
Clinical studies evaluating TCZ in patients
with ankylosing spondylitis have been
conducted, but they failed to demonstrate efficacy
]. Ongoing trials are under way to
assess TCZ in a range of disorders, such as hand
osteoarthritis, new-onset type 1 diabetes,
diabetic macular edema, myocardial infarction,
pulmonary arterial hypertension, psychiatric
disorders (e.g., schizophrenia, schizoaffective
disorder, and major depressive disorder),
primary Sjo¨gren’s syndrome, hepatocellular
carcinoma, chronic lymphocytic leukemia,
refractory dermatomyositis and polymyositis,
amyotrophic lateral sclerosis, graft-versus-host
disease, and human immunodeficiency virus
In summary, case reports and observational
or retrospective studies indicate that further
studies of TCZ may be appropriate for AOSD,
Behc¸et’s disease, other vasculitides, FMF, and
polychondritis. IL-6 is a pleotropic cytokine
with multiple effects and its inhibition is
leading to a large variety of clinical trials in multiple
diseases. Results from these trials will likely
guide further studies into other indications.
OTHER IL-6-TARGETED BIOLOGICS
Novel biologics that target IL-6 signaling are
undergoing clinical development in the RA
setting, including human anti-IL-6R alpha
(sarilumab, approved in the USA on 22 May 2017
for the treatment of RA) and anti-IL-6 cytokine
(olokizumab, sirukumab, and clazakizumab)
monoclonal antibodies. Interestingly, blockade
of the IL-6R (e.g., with TCZ or sarilumab) may
be associated with distinct clinical effects from
blockade of the IL-6 cytokine (e.g., with
sirukumab or clazakizumab). Use of a human
primary cell-based phenotypic screening system
(BioMAP ; DiscoverX, Fremont, CA, USA; now
part of Eurofins Scientific, Brussels, Belgium)
demonstrated that sirukumab and TCZ had
BioMAP phenotypic signatures that were
distinct from each other, suggesting that the
impact of TCZ on IL-6R signaling is distinct
from that of sirukumab [
preliminary evidence to date indicates that
these novel IL-6-targeted biologics show
promise with regard to their long-term efficacy and
Sarilumab has been approved in the USA and
EU for the treatment of patients with RA who
have an inadequate response to MTX or
csDMARDs. This approval was based on the
positive findings of two pivotal phase 3 clinical
trials, MOBILITY and TARGET, in which a total
of 1164 patients were exposed to sarilumab.
Sarilumab was investigated in MOBILITY, a
phase 3 trial of patients with RA who had
inadequate response to MTX [
with sarilumab 150 or 200 mg every 2 weeks in
combination with MTX was associated with
significant improvements compared with
placebo ? MTX, according to ACR20 response rates
at week 52 (58.0 and 66.4% vs. 33.4%), changes
from baseline to week 16 in HAQ-DI physical
function scores (- 0.53 and - 0.55 vs. - 0.29),
and the change from baseline to week 52 in the
Sharp/van der Heijde radiographic scores (0.90
and 0.25 vs. 2.78) (all P\0.0001). An OLE study
(EXTEND; ClinicalTrials.gov identifier
NCT01146652) of the MOBILITY trial also
demonstrated that sarilumab 200 mg provided
durable clinical response and stabilization of
radiographic progression at 3 years [
Furthermore, most patients who reduced their
dosage of sarilumab from 200 to 150 mg every
2 weeks in the OLE study demonstrated
sustained efficacy with regard to ACR20 response
rate (83.1%) and improvements in HAQ-DI
scores (- 0.68), along with continued
improvements in abnormalities in laboratory test
results, signs and symptoms of RA, and physical
The randomized, double-blind,
head-tohead, phase 3 MONARCH trial demonstrated
that sarilumab 200 mg was superior to
adalimumab with regard to the change from baseline
in DAS28-ESR (- 3.28 vs. - 2.20; P\0.0001) in
patients with RA and inadequate response to
Results of the randomized phase 3 TARGET
trial (ClinicalTrials.gov identifier
NCT01709578), which evaluated sarilumab ?
csDMARD therapy in patients with RA who
were inadequate responders to or intolerant of
TNF inhibitors, demonstrated that sarilumab
150 mg and 200 mg every 2 weeks were
associated with significant improvements in
ACR20 response rates at week 24 (56 and 61%
vs. 34%; both P\0.0001) and HAQ-DI physical
function scores at week 12 (- 0.50 and - 0.49
vs. - 0.29; both P\0.001), compared to
]. Analyses of the TARGET trial data
also showed significant and clinically
meaningful improvements from baseline in
patientreported outcomes (fatigue, morning stiffness,
pain, and work productivity) and significant
reductions in levels of biomarkers of bone
resorption and joint damage with sarilumab
]. Complete published results of these
analyses are pending. Published results are also
pending for the randomized phase 3
ASCERTAIN trial (ClinicalTrials.gov identifier
NCT01768572), which evaluated SC sarilumab
150 mg or 200 mg every 2 weeks and TCZ-IV
4 mg/kg increased to 8 mg/kg based on clinical
response in patients receiving background
csDMARDs who had an inadequate response to
or were intolerant of TNF inhibitors.
Preliminary results do not show clinically meaningful
differences between sarilumab 150 mg or
200 mg and TCZ with regard to
treatmentemergent AEs (67, 71, and 67%, respectively),
SAEs (2, 6, and 7%, respectively), or serious
infections (0, 2, and 2%, respectively) .
Olokizumab was evaluated in a phase 2b trial in
221 patients with RA who had an inadequate
response to TNF inhibitor therapy.
DAS28-CRPdefined improvements from baseline to week 12
for olokizumab versus placebo (- 1.16 to - 2.68
vs. - 0.19 to - 0.78; all P\0.05) were reported,
as were improvements in ACR20 response rates
(32.5–73.8% vs. 17.1–29.9%) [
second phase 2 study in 119 patients with RA
reported greater improvements in all
olokizumab treatment arms versus placebo for
DAS28-CRP-defined improvements from
baseline (all P\0.0001) and ACR20 rates (all
P\0.05) at week 12 . OLE studies of these
phase 2 trials demonstrated that olokizumab
was generally well tolerated and associated with
sustained reductions from baseline in disease
activity (DAS28-CRP) through 48 weeks
(olokizumab: - 0.60 to - 0.68; placebo: - 1.70
to - 1.76) [
]. A pooled analysis of these
phase 2 trials and their OLE studies indicated
that both Western and Asian patients receiving
olokizumab had greater improvements in
patient-reported outcomes compared with
placebo-treated patients at week 12; these
improvements were sustained through 40 and
48 weeks during the OLE studies. For example,
changes from baseline in HAQ-DI scores at
weeks 12 and 48 were consistently greater with
olokizumab than with placebo in 198 Western
patients (- 0.32 and - 0.45 vs. - 0.07 and
- 0.15) and in 105 Asian patients (- 0.41 and
- 0.60 vs. 0 and - 0.28) patients [
A phase 2 trial of sirukumab reported significant
improvements in ACR50 response rates at week
24 for sirukumab 100 mg every 2 weeks (n = 17)
versus placebo (n = 19) (26.7 vs. 3.3%; P\0.05)
and DAS28-CRP-defined improvements from
baseline for all sirukumab dose groups versus
placebo (2.0–2.2 vs. 1.0; all P\0.001) in
patients with RA and inadequate response to
The global, randomized, double-blind, phase
3 SIRROUND-H trial demonstrated significantly
greater DAS28-ESR-defined improvements from
baseline at week 24 with sirukumab 100 mg
every 2 weeks (n = 187) and sirukumab 50 mg
every 4 weeks (n = 186) versus adalimumab
every 2 weeks (n = 186) (- 2.96 and - 2.58 vs.
- 2.19; P\0.001 and P = 0.013, respectively) in
biologic-naive patients with RA who were
intolerant of or inadequate responders to MTX.
However, the second co-primary end point
(ACR50 at week 24) was not met (35.3 and
26.9% vs. 31.7%; P = 0.464 and P = 0.306,
respectively). Rates of SAEs were 2.7% for
sirukumab 100 mg, 7.0% for sirukumab 50 mg,
and 4.3% for adalimumab [
Although substantial evidence of efficacy is
available for sirukumab in the RA setting, the
U.S. FDA rejected its regulatory approval in
September 2017 based on safety concerns over
serious infections, malignancy, major adverse
cardiac events, and abnormalities in laboratory
tests, including a decreased neutrophil count. A
trend of increased overall mortality for
sirukumab over placebo was reported, which was
mainly associated with major adverse cardiac
events, infection, and malignancy [
Clazakizumab with or without MTX was
evaluated in a phase 2b trial in 418 patients with RA
and an inadequate response to MTX. Significant
improvements in ACR20 response rates were
observed for monotherapy with clazakizumab
100 and 200 mg and for combined
clazakizumab 25, 100, and 200 mg ? MTX therapy
compared to MTX monotherapy (55.0, 61.0,
76.3, 73.3, and 60.0% vs. 39.3%; all P\0.05)
The anti-IL-6R nanobody vobarilizumab
(ALX0061) is currently being evaluated as
monotherapy (150 mg every 4 weeks, 150 mg
every 2 weeks, or 225 mg every 2 weeks) in a
randomized, head-to-head, phase 2b trial versus
TCZ in patients with moderate to severe RA who
were intolerant to MTX or for whom continued
MTX treatment is inappropriate [
]. At week
12, ACR20 response rates were similar between
the three vobarilizumab dose groups and TCZ
(73–81 vs. 78%), although DAS28-ESR-defined
remission rates appeared to be higher with the
vobarilizumab 150 mg every 4 weeks and
225 mg every 2 weeks dosage groups versus TCZ
(34 and 40% vs. 25%) [
In summary, two anti-IL-6R biologics have
been approved for the treatment of RA, namely,
TCZ and sarilumab, and multiple agents
blocking the IL-6 signaling pathway are in
development in this constantly changing field.
Available data to date suggest that the newer
agents may have similarities to TCZ; however,
this inference is based mainly on data presented
in abstract format, and it would therefore be
premature and potentially misleading to
compare efficacy and safety among these
IL-6-targeted therapies. More data on the newer agents
are eagerly awaited to inform physicians on the
treatment of patients with RA and other
Tocilizumab is the first-in-class humanized
antiIL-6Ra monoclonal antibody to undergo global
clinical development, resulting in its approval
for the management of RA, Castleman’s disease,
sJIA, pJIA, and GCA. In the RA setting, approval
of TCZ was based on data from five pivotal
phase 3 clinical trials that demonstrated its
efficacy and safety in a range of patient
populations, including inadequate responders to
MTX and inadequate responders to TNF
inhibitors. This review emphasizes recent
developments with TCZ and other IL-6-targeted
biologics; TCZ monotherapy has been
evaluated, including in the early RA setting, and an
SC formulation of TCZ was developed.
Longterm safety studies have been encouraging, with
no new toxicities identified and no difference in
the frequencies of AEs and SAEs observed
compared with those reported in pre-approval
studies. Results reported to date suggest that
TCZ has low immunogenicity.
TCZ has recently been approved for the
treatment of GCA and is also being investigated
for the treatment of SSc. However, TCZ was
found not to be effective for the treatment of
ankylosing spondylitis. Other off-label
indications in which TCZ is being evaluated include
RA-associated vasculitis, Takayasu arteritis,
AOSD, PMR, Behc¸et’s disease, amyloidosis, FMF,
Schnitzler’s syndrome, and polychondritis.
However, limited data have been published for
these diseases, and future prospective studies
may determine whether there is a role for TCZ
in the treatment of these diseases. Another IL-6
therapy, sarilumab, has been recently approved
for the treatment of patients with RA who are
inadequate responders to MTX/csDMARD, with
comparable results to adalimumab. However,
long-term data are still needed for this drug.
Novel IL-6 signaling-targeted biologics being
developed have shown promise in the RA
setting. However, the current lack of published
data in the literature for these agents precludes
accurate comparisons to data for TCZ.
Welldesigned clinical trials are needed to establish
the efficacy and safety profiles of these newer
agents; in particular, direct comparator studies
to TCZ are needed.
Funding. No funding was received for article
processing charges. Support for medical writing
assistance was provided by F. Hoffmann–La
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
manuscript, take responsibility for the integrity
of the work as a whole and have given final
approval for the version to be published.
Medical Writing, Editorial, and Other
Assistance. Editorial assistance in the
preparation of this manuscript was provided by
Maxwell Chang and Sara Duggan, Ph.D., of
ApotheCom (Yardley, PA, USA). Support for this
assistance was funded by F. Hoffmann–La
Roche, Basel, Switzerland.
Disclosures. Andrea Rubbert-Roth reports
honoraria and advisory board fees from Roche
and honoraria from Chugai during the conduct
of the submitted work as well as honoraria and
advisory board fees from Sanofi, Bristol-Myers
Squibb, Pfizer, MSD, and Eli Lilly, and honoraria
from UCB and AbbVie outside of the submitted
work. Daniel E. Furst reports grant/research
support from AbbVie, Actelion, Amgen,
BristolMyers Squibb, Corbus, National Institutes of
Health, Novartis, Pfizer, and Roche/Genentech
and is a consultant for AbbVie, Actelion,
Amgen, Bristol-Myers Squibb, Cytori, Novartis,
Pfizer, and Roche/Genentech outside of the
submitted work. J. Michael Nebesky is an
employee of and reports personal fees from F
Hoffmann–La Roche Ltd during the conduct of
the work and outside of the submitted work.
Angela Jin is an employee of Genentech Inc.
Erhan Berber is an employee of and owns stock
and stock options in Genentech Inc.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by any of the
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