The n e w e ng l a n d j o u r na l
clinical therapeutics
From the Department of Rheumatology,
Kings College London School of Medi-
cine, Weston Education Centre, Kings
College (D.L.S., G.H.K.); the Department
of Rheumatology, Kings College Hospital
(D.L.S.); and the Department of Rheu-
matology, University Hospital Lewisham
(G.H.K.) — all in London.
N Engl J Med 2006;355:704-12.
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704
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of m e dic i n e
Tumor Necrosis Factor Inhibitors
for Rheumatoid Arthritis
D.L. Scott, M.D., and G.H. Kingsley, M.B., Ch.B., Ph.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors’ clinical recommendations.
Rheumatoid arthritis developed in a 25-year-old woman, who was found to have a
positive rheumatoid factor (150 IU per milliliter); she had no periarticular radiologic
erosions or extraarticular disease. Oral methotrexate was started and incrementally
increased to 20 mg weekly. Subsequently, sulfasalazine (Salazotyrin, Pharmacia;
Azulfidine, Pfizer) was added and gradually increased to 2 g daily. Despite six months
of combination therapy, she had 10 swollen and tender joints and an elevated erythro-
cyte sedimentation rate (54 mm per hour). Twelve months after onset, we were asked
to evaluate her for possible tumor necrosis factor (TNF) inhibitor therapy.
The Cl inic a l Probl e m
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis. RA occurs world-
wide, and 75 percent of those affected are women. Its prevalence among adults is
approximately 1 percent but varies across racial and ethnic groups, reflecting the
prevalence of predisposing genes such as the HLA-DR4 allele.
Joint destruction, characterized by progressive bone erosion, is the dominant cause
of disability in RA. A minority of patients have extraarticular features such as
rheumatoid nodules and lung disease. RA is associated with increased risks of coro-
nary artery disease, infection, and lymphoma as well as reduced life expectancy.1
Patients with RA and society at large incur substantial direct and indirect costs
for medical and social care and for loss of employment. One systematic review of
the costs of RA that predated the introduction of “biologic” therapies showed very
high costs — $98 million to $122 million per million population — that were
similar in developed nations.2
Pathoph ysiol o gy a nd Effec t of Ther a py
The cause of RA is unknown, but a current model3 is shown in Figure 1. It is likely
that, in genetically predisposed persons, an infective agent or another stimulus
binds to toll-like receptors on peripheral dendritic cells and macrophages. This trig-
gers a rapid response by the innate immune system involving cytokines and other
inflammatory mediators, complement, natural killer cells, and neutrophils.
Dendritic cells then migrate to lymph nodes, where they activate the adaptive
immune system by presenting antigen to T cells. T-cell activation requires two
signals: signal 1 is generated by antigen (major-histocompatibility-complex–bound
n engl j med 355;7 www.nejm.org august 17, 2006
The New England Journal of Medicine
 clinical ther apeutics

Figure 1. Pathophysiological Role of Cytokines and Other Mediators and Their Inhibitors in RA.
In the current model of the pathogenesis of RA, an infective agent or other stimulus binds to receptors on dendritic
cells, activating the innate immune system. Dendritic cells migrate into lymph nodes, presenting antigen to T cells,
which are activated by the dual signal of antigen presentation and costimulation through CD28. Activated T cells
proliferate and migrate into the joint. In the synovial tissue, T cells produce interferon-γ and other proinflammatory
cytokines that stimulate macrophages and fibroblasts as well as chondrocytes, osteoclasts, and B cells. Activated
macrophages and fibroblasts release a variety of cytokines, including TNF-α. TNF-α is a central component in the
cascade of cytokines, stimulating the production of additional inflammatory mediators and the further recruitment
of immune and inflammatory cells into the joint. Infliximab and adalimumab are monoclonal anti–TNF-α antibodies
that bind to TNF-α with high affinity and prevent it from binding to its receptors. Etanercept is a fusion protein con-
sisting of two p75 TNF receptors that are linked to the Fc portion of human IgG1. It also binds to TNF-α and prevents
it from interacting with its receptors on cell surfaces.

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 The n e w e ng l a n d j o u r na l
peptide on the antigen-presenting cell stimulates
the T-cell receptor), whereas signal 2 is generated
by CD28 costimulation (CD80 or CD86 on the
antigen-presenting cell interacts with CD28 on the
T cell). These activated T cells proliferate and mi-
grate into the joint, where they stimulate a multi-
molecular immune–inflammatory cascade.
T cells produce interferon-γ and other pro-
inflammatory cytokines, which stimulate macro-
phages, fibroblasts, chondrocytes, and osteoclasts.
Activated macrophages and fibroblasts release
tumor necrosis factor α (TNF-α), interleukin-1,
interleukin-6, interleukin-15, interleukin-18, and
other proinflammatory cytokines that stimulate
the production of additional inflammatory medi-
ators (chemokines, prostaglandins), proteases, and
growth factors and activate neutrophils, B cells,
and endothelial cells. This endothelial transfor-
mation perpetuates the immune response by en-
hancing cell recruitment to the joint. Finally, joint
damage, associated with the development of lo-
cally invasive pannus tissue, occurs through the
actions of proteases, growth factors, and activat-
ed osteoclasts.
TNF-α, a central component in the cascade of
cytokines induced in RA, exerts its effects through
binding to two receptors, the type 1 TNF receptor
(p55) and the type 2 TNF receptor (p75), which
are found on immune, inflammatory, and endo-
thelial cells. The rationale for choosing TNF-α
as a target is that it is found in high concentra-
tion in the rheumatoid joint, that in vitro experi-
ments have shown that it induces other (inflam-
matory) cytokines in the synovial cytokine network,
and that in experimental models arthritis is sup-
pressed by TNF inhibitors.
TNF inhibitors were first licensed for clinical
use in 1998; three have been approved for the
treatment of RA (Fig. 1). Infliximab (Remicade,
Centocor) is a chimeric (human–murine) IgG1
anti–TNF-α antibody that is administered intra-
venously. It binds with high affinity to soluble and
membrane-bound TNF-α and inhibits its effect
by blocking TNF-α–receptor interactions. Unlike
the other agents, infliximab is also cytotoxic for
TNF-expressing cells. Etanercept (Enbrel, Amgen
and Wyeth) is a recombinant soluble p75 TNF
receptor:Fc fusion protein given subcutaneously.
It is a dimer of covalently bound receptors of the
higher-affinity type 2 TNF receptor (p75) linked
to the Fc portion of human IgG1. Etanercept binds
to TNF-α, preventing it from interacting with its
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of m e dic i n e
receptor; unlike the other two agents, it also tar-
gets TNF-β (lymphotoxin). Adalimumab (Humira,
Abbott) is a recombinant humanized monoclo-
nal anti–TNF-α antibody that is administered
subcutaneously. It binds to human TNF-α with
high affinity and, as a consequence, stops the
cytokine from binding to its receptors.
Cl inic a l E v idence
TNF inhibitors have been evaluated in a series of
randomized, controlled trials enrolling nearly
6000 patients with RA.4-18 In most of the trials,
these agents were studied in comparison with, or
in addition to, methotrexate. In five such trials,
patients with early RA who had not been treated
with methotrexate were studied, whereas in six
others, patients with established RA who had not
had a response to methotrexate were studied.
The clinical response to treatment of RA is
often assessed by determining how frequently
patients achieve substantial clinical improvement
with therapy. One standard measure of improve-
ment is the proportion of patients who have 70
percent or greater improvement according to
seven clinical and laboratory measures of dis-
ease activity according to the American College
of Rheumatology (ACR). Such patients are des-
ignated as having ACR-70 responses. ACR-70 re-
sponses were found in 19 to 21 percent of pa-
tients receiving methotrexate monotherapy in
trials in early RA but in 33 to 40 percent of those
receiving TNF inhibitors combined with metho-
trexate. In established RA, ACR-70 responses oc-
curred in fewer than 5 percent of patients receiv-
ing methotrexate monotherapy but in 10 to 27
percent of those receiving TNF inhibitors com-
bined with methotrexate.
TNF inhibitors substantially reduce the erosive
damage assessed on radiography19 and with mag-
netic resonance imaging.20 They also decrease the
disability self-assessed with the use of instru-
ments such as the Health Assessment Question-
naire21 and improve the quality of life assessed
with the use of the Medical Outcomes Study 36-
item Short-Form General Health Survey.22 Patients
describe highly positive overall effects.23
In early and established RA, TNF inhibitors
in combination with methotrexate, the most wide-
ly used disease-modifying antirheumatic drug
(DMARD), are more effective than monothera-
py with either methotrexate or a TNF inhibitor.
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 clinical ther apeutics
A crucial question is whether TNF inhibitors com-
bined with methotrexate are better than combi-
nations of established DMARDs. Since there has
been only a single head-to-head study,17 which
showed only a modest benefit, the question is
largely unanswered.
Cl inic a l Use
Treatment of RA is typically initiated with non-
steroidal antiinflammatory drugs and simple
analgesics to relieve pain and stiffness. DMARDs,
which improve symptoms and reduce erosive dam-
age, are initiated as early as possible. Standard
conventional DMARDs include methotrexate, sul-
fasalazine, leflunomide (Arava, Aventis), hydroxy-
chloroquine (Plaquenil, Sterling Winthrop), and
cyclosporine (Sandimmune, Novartis); methotrex-
ate is the most widely used. There is increasing em-
phasis, especially in severe disease, on using com-
binations of two or more conventional DMARDs.24
Steroids (intraarticular, intramuscular, or oral)
are often used to manage disease flares.
TNF inhibitors are usually given to patients
with active RA in whom there has not been a
satisfactory response to one or more conventional
DMARDs such as methotrexate. Views differ on
what constitutes active RA.25 One definition is six
or more tender and three or more swollen joints
together with either an erythrocyte sedimentation
rate greater than 30 mm per hour or at least 45
minutes of morning stiffness. Another definition
is a disease activity score of more than 5.1 (range
of scores, 0 to 10, with higher scores indicating
more active disease), although some experts have
expressed concern about the inherent variability
of these scores.26 Many rheumatologists rely on
clinical opinion alone.
The concept of treatment failure with DMARDs
is also inadequately defined. Many rheumatolo-
gists use clinical opinion alone, whereas others
rely on predetermined definitions. In the United
Kingdom, such failure is defined as “failure to
respond to or tolerate adequate therapeutic trials
of at least two standard DMARDs,” with an ade-
quate therapeutic trial involving at least six months
of therapy unless limited by significant toxic ef-
fects.27 This strict definition is not universally
accepted.
Prior to the initiation of TNF inhibitor therapy,
patients should be screened for latent tuberculo-
sis, and antituberculosis prophylaxis should be
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considered for patients at risk.28 Patients should
also be evaluated for evidence of other preexist-
ing infections, which may constitute contraindi-
cations to treatment. TNF inhibitors should prob-
ably be avoided in the presence of certain chronic
infections such as with hepatitis B; however,
etanercept has been used safely in small series
of patients with hepatitis B and hepatitis C infec-
tions. Practitioners should exercise extreme cau-
tion when considering whether to prescribe a TNF
inhibitor for a patient with a coexisting infection
and seek expert advice. Live vaccination is con-
traindicated in patients receiving TNF inhibitors
as well as in those taking some other DMARDs
such as methotrexate; where an alternative non-
live vaccine is not available, consideration should
be given to vaccination before starting TNF in-
hibitor therapy.
Other precautions that should be taken before
commencing TNF inhibitors include ruling out
significant concomitant illness (including those
noted in the section on Adverse Effects). Although
initial complete blood counts and biochemical
profiles are not mandatory, they are generally
used to rule out serious coexisting diseases and
because patients taking DMARDs such as metho-
trexate require blood monitoring.
There are no clinical trials comparing one
TNF inhibitor with another. The choice of agent
therefore depends on other factors, including pa-
tients’ convenience, access to treatment, and pa-
tients’ preferences. Infliximab requires infusion
intravenously every four to eight weeks performed
by a health care professional. The usual dose is
3 mg per kilogram of body weight; some patients
require higher doses. Infliximab is given with
methotrexate to prevent the formation of human
antichimeric antibody (HACA), since HACA in-
creases the likelihood of infusion reactions and
accelerates infliximab clearance. Etanercept and
adalimumab are self-administered by subcuta-
neous injection. Etanercept is given at a dose of
25 mg twice weekly or 50 mg weekly, and adalim-
umab is given at a dose of 40 mg every two
weeks. Although concomitant methotrexate ther-
apy is not essential with the use of these agents,
combination therapy is more effective and is now
recommended for adalimumab, unless there are
contraindications.
As noted, TNF inhibitors have been studied
primarily in comparison with, or in addition to,
methotrexate. There are no trial data on the use of
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 The n e w e ng l a n d j o u r na l
TNF inhibitors with other conventional DMARDs,
but observational studies suggest that this is prac-
tical and effective when methotrexate cannot be
used. The combination of TNF inhibitors with
new biologic agents such as anakinra (Antril,
Synergen) (an interleukin-1–receptor antagonist)
and abatacept (Orencia, Bristol-Myers Squibb) (a
T-cell–costimulation inhibitor) is not recommend-
ed, since studies have shown an increased risk
of serious infections.
DMARDs such as methotrexate require rou-
tine safety monitoring to detect blood and liver
toxicity, and monitoring should continue when
these agents are prescribed along with TNF in-
hibitors. Although there are no specific monitor-
ing requirements for the use of TNF inhibitors,
patients should regularly undergo assessment for
clinical evidence of serious side effects such as
infection and should be warned to contact a phy-
sician immediately in the event of fever or other
symptoms of infection.
TNF inhibitors are expensive, with annual costs
ranging from $10,000 to $25,000 or more per
patient, depending on the circumstances and the
country. Data supplied by the manufacturers sug-
gest that TNF inhibition is cost-effective accord-
ing to a commonly applied threshold of $50,000
per quality-adjusted life-year gained.29,30 However,
reports commissioned by regulators and reports
based on independent data both suggest that they
are substantially less cost-effective.31,32 The rela-
tive expense of TNF inhibitors makes their uni-
versal use impractical. Conversely, cost-effective-
ness studies cannot examine the moral case for
ensuring that they remain a potential treatment
option.
Treatment with TNF inhibitors should be
stopped if there is evidence of drug-related toxic
effects or no evidence of efficacy within three to
six months. The definition of clinical efficacy is
also contentious. One European view suggests that
a fall in the score for disease activity of more
than 1.2 indicates efficacy. If treatment with one
TNF inhibitor is stopped because of inefficacy or
an adverse event, there is some evidence that an
alternative TNF inhibitor can be effective. Tempo-
rary withdrawal of treatment is also required with
severe intercurrent infection and in the event of
pregnancy. Many experts recommend temporar-
ily stopping TNF inhibitors at the time of sur-
gery because of concern about infections, although
the evidence for doing so is incomplete.
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A dv er se Effec t s
Common minor adverse events include injection-
site reactions with etanercept and adalimumab and
infusion reactions with infliximab.33 Rare seri-
ous adverse events include optic neuritis, exacer-
bations of previously quiescent multiple sclerosis,
aplastic anemia, and interstitial lung disease; lupus-
like syndromes and hepatotoxicity may also occur.
Serious infections are a particular concern,34-36
especially respiratory and skin infections. TNF
inhibitors should be stopped in the presence of
serious infections. Susceptibility to intracellular
pathogens may be increased, and primary tuber-
culosis and reactivation of prior tuberculosis are
specific problems.37,38 As noted, patients should
be screened for tuberculosis before the initiation
of therapy.
The overall risk of cancer is controversial. The
only systematic review, which focused on random-
ized, controlled trials involving infliximab and
adalimumab but not etanercept, reported a dose-
related increased risk of cancer.36 In contrast,
national registries have not yet found an increase
in solid cancers after treatment with TNF inhibi-
tors.39,40 An increase in lymphomas has been re-
ported with all TNF inhibitors.36,41-43 However,
because there is a preexisting association of lym-
phomas with severe RA and systemic inflamma-
tion,44 the exact contribution of therapy with TNF
inhibitors is difficult to dissect. Given these un-
certainties, it seems sensible to use extreme cau-
tion when considering the use of TNF inhibitors
in many patients with a history of malignant dis-
ease, or even to avoid them altogether, and to warn
patients that the risk of cancer with this form of
therapy remains unknown. Table 1 summarizes
the risks of serious infection and cancer.
Since infliximab increases mortality when used
to treat severe heart failure in patients without
arthritis,45 TNF inhibitors should be used cau-
tiously, if at all, when mild heart failure is pres-
ent and are best avoided when heart failure is
severe. However, there is no evidence that TNF
inhibitors increase the risk of new-onset cardiac
failure in patients with RA.46,47
Patients are usually advised not to conceive
while taking TNF inhibitors and to avoid these
treatments during pregnancy or lactation. To date
no actual adverse events have been described in
those pregnancies that have occurred in patients
taking TNF inhibitors.48
www.nejm.org august 17, 2006
 Table 1. Serious Adverse Events Associated with TNF Inhibitors.*

Evidence Infection Cancer

Serious Infections
Meta-analysis of clinical trials of Patients, 3.6%
infliximab and adalimumab36† Controls, 1.7%
NNH, 59
National registries‡ Infliximab, 5.2/100 PY
United Kingdom35,37 Etanercept, 5.3/100 PY
Adalimumab, 6.3/100 PY
Sweden38,40,43
Tuberculosis All Cancers Solid Tumors Lymphoma
Patients, 0.9%
Controls, 0.2%
NNH, 154
Patients receiving all
agents, 0.86/100 PY
Controls, 1.42/100 PY
Infliximab or etanercept Patients receiving all Patients receiving all
(relative risk, 4.1) agents, 0.9 SIR agents, 2.9 SIR
Controls, 1.1 SIR Controls, 2.0 SIR

n engl j med 355;7

Germany34 Infliximab, 6.2/100 PY
Etanercept, 6.4/100 PY
Controls, 2.3/100 PY
Other
Consensus37 Infliximab, 0.07/100 PY

www.nejm.org
Etanercept, 0.02/100 PY
Adalimumab, 0.27/100 PY
clinical ther apeutics

U.S. national databank41§ Patients receiving all

agents, 2.9 SIR
Controls, 1.5 SIR

The New England Journal of Medicine

Comment Increased risk of serious infections, including tuberculosis, Increased overall risk of cancer shown in meta-analysis of clinical trials, but too

august 17, 2006

with all agents in all types of study few cases to differentiate between solid tumors and lymphomas. National reg-
istries and U.S. databank show no increase in overall risk of cancer or solid tu-
mors but an increased risk of lymphoma.

Copyright © 2006 Massachusetts Medical Society. All rights reserved.

* NNH denotes number needed to harm, PY patient-years, and SIR standard incidence ratio.
† Control subjects were patients who underwent randomization but did not receive TNF inhibitors.
‡ In the U.K. and German registries, the controls were patients with RA who were treated with disease-modifying antirheumatic drugs. In the Swedish registry, the controls were a cohort
with early RA; data on an inpatient RA cohort were also available.
§ Controls were patients with RA who were treated with methotrexate only; data on patients with RA who did not receive methotrexate were also available.

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709
 The n e w e ng l a n d j o u r na l
A r e a s of Uncer ta in t y
Like other randomized, controlled trials in RA,
trials of TNF inhibitors have enrolled patients
with active RA. The generalizability of the results
to patients with milder disease in routine practice
remains contentious.24,49 Equally important is
concern regarding adverse events. In the United
Kingdom, Sweden, and other European countries,
long-term national registries have not identified
unexpected major toxic effects during the first
five years of observation, but caution remains es-
sential. Reducing TNF inhibitors when patients
have a sustained good response appears to be ra-
tional, but its feasibility has not been examined
in established RA and there is only minimal evi-
dence in its favor in early RA.20
The relative advantage of TNF inhibition com-
pared with optimal combinations of conventional
DMARDs has also not been adequately evaluated.
Systematic reviews suggest small benefits of TNF
inhibition.24 Only one randomized, controlled
trial of early RA compared combination treat-
ment including TNF inhibition with combination
DMARDs.17 The study reported sustained low
disease activity in 81 percent of patients treated
with a TNF inhibitor plus methotrexate, as com-
pared with 73 percent of patients who received
optimal combination treatment with the use of
methotrexate, sulfasalazine, and prednisolone,
suggesting only limited benefit from TNF inhibi-
tion. In contrast, 39 percent of the patients treated
with methotrexate monotherapy had sustained
low disease activity.
TNF inhibitors are not the immunologic “mag-
ic bullet” that cures RA; consequently, their use
needs constant reassessment, especially as com-
parative data with combination DMARDs and
new biologic agents become available. There is
growing evidence that new biologic agents such
as abatacept, rituximab (Rituxan, Genentech and
Biogen Idec), and tocilizumab (Actemra, Roche)
are effective and can be used in patients who do
not have a response to TNF inhibition.
Finally, these exciting advances in drug treat-
ment should not obscure the contributions of
nondrug treatment methods to the overall man-
agement of RA. These methods include education,
exercise, psychological approaches, and joint-
replacement surgery.
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of m e dic i n e
Guidel ine s
Many international groups,50 specialist socie-
ties,27,51 and regulatory bodies52 have produced
guidelines for the use of TNF inhibitors in pa-
tients with RA. Most of these guidelines recom-
mend that TNF inhibitors should be used in pa-
tients with active RA who have not had a response
to conventional DMARDs, particularly methotrex-
ate. Definitions of active RA and an inadequate
response to DMARDs differ. A rigid approach,
exemplified by British guidelines,52 requires that
patients have no satisfactory response to two
DMARDs before receiving TNF inhibitors. Other
countries, including the United States, have ad-
opted more flexible approaches.
R ec om mendat ions
Four evidence-based approaches have been con-
sidered. Since none of them were a definite best
option, the advantages and disadvantages were ex-
plored with the patient described in the vignette.
First, she could change from oral methotrexate to
subcutaneous methotrexate, which is slightly more
effective. Second, a new DMARD, such as leflu-
nomide, could be used. Third, she could change
to an evidence-based combination such as meth-
otrexate–sulfasalazine–hydroxychloroquine or
methotrexate–cyclosporine; aggressive combina-
tions with high-dose prednisolone were not con-
sidered, because they have been studied only as
initial treatment for early arthritis. Finally, the pa-
tient fulfilled U.K. guidelines for starting a TNF
inhibitor, which was her preferred option. She
started etanercept because she preferred frequent
self-administration. She continued to take meth-
otrexate at a dose of 20 mg weekly; sulfasalazine
was stopped.
Patient-related factors, such as convenience,
acceptability to the patient, and risks (including
risks to future pregnancy), and issues related to a
patient’s health care system, such as cost-effec-
tiveness and access to treatment, all influence
the decision of whether to start a TNF inhibitor
and the choice of agent. We recommend that,
since there is no clear best choice on medical
grounds, priority should be given to the patient’s
preference from among the options available lo-
cally. Patients should be given sufficient infor-
www.nejm.org august 17, 2006
 clinical ther apeutics

mation to allow them to make genuinely informed grants from Amgen, Schering-Plough, and Sanofi-Aventis. His
department also receives grants from the Arthritis Research
choices. Campaign (ARC), the Medical Research Council, the Nuffield
Dr. Scott reports having received consulting fees from Novar-
Foundation, and the Myositis Support Group. Dr. Kingsley reports
tis and Sumitomo Chemical and lecture fees from Wyeth, Sanofi-
having received grants from the ARC and the Nuffield Founda-
Aventis, Merck, and Novartis. His department has received
tion. No other potential conflict of interest relevant to this arti-
funding for clinical trials from Pfizer, Q-Med, AstraZeneca,
cle was reported.
Sumitomo Chemical, and Roche and unrestricted clinical research

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