European Journal of Pharmacology 623 (2009) S1–S4

Contents lists available at ScienceDirect

European Journal of Pharmacology

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Ten years of infliximab (Remicade®) in clinical practice: The story from

bench to bedside☆
Freddy Cornillie
Centocor BV, Medical Affairs Dept., Interleuvenlaan 62, 3001 Heverlee, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Infliximab was first introduced in Europe in 1999 for Crohn's disease. During the following decade major
Accepted 30 September 2009 progress was made in the understanding of the pathophysiology of inflammatory bowel diseases and
Available online 21 Ocotober 2009 treatment with infliximab. Today, treatment algorithms with anti-TNF and optimization of anti-TNF use in
daily clinical practice are important research topics in Crohn's disease and ulcerative colitis. TNF blockade has
Keywords:
also changed the rheumatology practice during the last 10 years. Earlier treatment, combination with disease
Infliximab
Tumor necrosis factor
modifying anti-rheumatic drugs, and identification of risk factors of poor prognosis are hot research topics
Monoclonal antibody today. The introduction of infliximab (among other biological therapies) has thus changed the way how
Inflammatory bowel disease inflammatory bowel diseases and rheumatoid conditions are treated. More importantly, infliximab has
Rheumatoid arthritis offered significant improvement of the quality of life of many patients. In addition, we currently collect data
indicating that infliximab is changing the natural course of these inflammatory diseases.
© 2009 Elsevier B.V. All rights reserved.

Contents

1. Where do we go from here? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. S3
Disclosure
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S3
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S3

The development of new therapeutic agents for immune mediated
inflammatory diseases such as rheumatoid arthritis, ankylosing
spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, and ulcera-
tive colitis started with the introductions of corticosteroids and
sulfasalazine (mid 1950ies), immunosuppressive agents such as
methotrexate, azathioprine, 6-MP (6-mercaptopurine), aminosali-
cyaltes (early 1980ies), and cyclosporine (mid 1990ies).
By then, Georges J.F. Köhler and César Milstein developed the
(mouse) monoclonal antibody technology, and – together with Niels J.
Jerne – were awarded the 1984 Noble Prize for Physiology or Medicine
for their “theories concerning the specificity in development and
control of the immune system and the discovery of the principle for
production of monoclonal antibodies” (Kohler and Milstein, 1975).
☆ This supplement of the European Journal of Pharmacology will review the
immunologic and clinical developments of infliximab (Remicade®) before and after
its market authorization in USA (1998) and Europe (1999). It is indeed 10 years ago
when the European authorities approved infliximab as the first innovative biologic
therapy for Crohn's disease.
This supplement wants to add a scientific summary contribution to the “celebration”
of this anniversary.
E-mail address: fcornill@its.jnj.com.
Antibody production technologies have since evolved (Clark, 2007),
and chimeric recombinant monoclonal antibodies (such as inflix-
imab), CDR grafted humanized antibodies (such as efalizumab), and
fully human antibodies (synthetic antibodies by phage display such as
adalimumab and transgenic human antibodies such as golimumab)
have now entered the clinic in several therapeutic fields. Today, these
biological therapies have changed clinical practice and outcomes in
several immune mediated inflammatory diseases. Blockade of TNF has
played a major role in this clinical evolution.
Early immunology research at the Kennedy Institute of Rheumatology
in London demonstrated that TNF, among other cytokines and chemo-
kines, was a primary driver of the inflammatory responses observed in
arthritic joints of animal models and in human. Marc Feldmann et al.
“dissected” the synovial tissue and the components of the synovial fluid,
and described elevated expression of TNF in both the synovial tissue and
synovial fluid of inflamed joints (Feldmann et al., 1996).
At Centocor, D. Knight et al. had developed by then a chimeric anti-
TNF monoclonal antibody, infliximab (Knight et al., 1993). This antibody
with high affinity (1.8 × 10− 9 kDa), high avidity, and absolute specificity
showed to be safe in preclinical testing. First in-human studies were run
in healthy volunteers to identify therapeutic dosages needed to block

0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2009.10.023
S2 F. Cornillie / European Journal of Pharmacology 623 (2009) S1–S4
free circulating TNF in serum. Therefore, healthy volunteers received
a single infusion of 0.01, 0.1. 1.0, 10 mg/kg infliximab or placebo
followed by 4 ng/kg E. coli toxin (to release TNF). This experiment
showed that doses of 1.0 mg/kg and 10.0 mg/kg of infliximab
resulted in complete binding of free TNF from the serum. Binding
of infliximab onto circulating TNF makes the latter biologically
inactive. Additional pharmacology studies showed that infliximab
also binds to membrane-bound (and biologically active) TNF
expressed on activated macrophages, T cells, and dendritic cells,
and that this binding can induce cell lysis of the activated cells
through antibody dependent cellular cytotoxicity (ADCC), reverse
signaling and/or apoptosis in vitro (Shen et al., 2005), and in vivo
(Van den Brande et al., 2007).
The latter mechanism of cell killing may play an important role in
mucosal healing processes observed in inflammatory bowel disease
patients treated with infliximab (discussed in more detail in the
inflammatory bowel disease contribution of G. van Assche et al., this
issue). Simultaneously, other molecules inhibiting TNF were devel-
oped, e.g. enbrel, a construct of 2 soluble p75 TNF receptors linked to
the Fc part of an IgG1molecule (Fig. 1).
The research team at the Kennedy Institute of Rheumatology was
able to treat the first rheumatoid arthritis patients with infliximab
in a randomized controlled trial (Elliot et al., 1994). Infliximab
proved to be very effective in controlling joint inflammation as
evidenced by a quick reduction of the number of swollen and tender
joints as well as rapid normalization of C reactive protein (CRP)
values with no effect of placebo infusions. These early encouraging
results accelerated a full clinical development program of infliximab
in rheumatoid arthritis. Indeed, the phase III pivotal trials ATTRACT
(Maini et al., 2004), ASPIRE (St.Clair et al., 2004), and the phase IV
START trial (Westhovens et al., 2006) followed each other quickly.
Interestingly, the major finding of ATTRACT trial was that blockade
of the biological activity of TNF resulted in inhibition of progression
of structural damage of arthritic joints. Furthermore, the radio-
graphic results did not correlate well with the clinical findings, and
also patients who did not reveal an American College of Rheuma-
tology (ACR) response had inhibition of structural joint damage
progression.
It was therefore concluded that rheumatoid patients would need
infliximab treatment earlier in their disease course, i.e. before joint
damage can ever happen. The ability to arrest progression of
structural joint damage was confirmed in the ASPIRE trial. In this
study, methotrexate-naive patients with a median disease duration of
0.8–0.9 years (mean) were included (St.Clair et al., 2004).
Fig. 1. Comparison of molecular structures of infliximab chimeric monoclonal antibody and etanercept p75 TNFR-Fc fusion protein.
Apart from these major findings, the early trial results in
rheumatoid arthritis learned that infliximab and methotrexate have
synergistic activity, and that combination therapy is the best option
for patients treated with anti-TNF agents. Addition of methotrexate to
infliximab treatment also resulted in reduction of the rate of anti-
infliximab antibody production (Maini et al., 1998).
More recently, research has focused on the possibility to screen
rheumatoid arthritis patients for their risk of rapid radiographic
progression (Vastesaeger et al., 2009). Selection of those patients at
high risk and with greatest possible benefit is indeed an important
treatment and health economic objective. Early treatment of
rheumatoid arthritis patients aiming at induction of low disease
activity state and remission should become the standard treatment
goal. Today, new treatment strategies are studied and applied in clinic.
The BeSt trial showed that early treatment with infliximab guided by
tight control towards remission delivers long-term clinical and
radiological benefit with 18% of patients in sustained remission off
drug 4 years after infliximab and methotrexate treatment initiation
(van der Kooij et al., 2009).
In rheumatoid arthritis, we have thus moved from treating signs
and symptoms towards changing the natural course of disease and
selecting the patients with best possible outcomes. That's quite a step
forward in 2 decades of clinical progress.
Meanwhile, small investigator initiated studies in psoriatic
arthritis (Antoni et al., 2008) and ankylosing spondylitis (Braun
et al., 2002) showed excellent efficacy of infliximab in both skin and
joint symptoms of psoriatic arthritis and of axial as well as of
peripheral arthritis symptoms in ankylosing spondylitis. Pivotal phase
III trials proved the clinical findings of these smaller proof-of-concept
studies in both psoriatic arthritis (Antoni et al., 2005), and ankylosing
spondylitis (Braun et al., 2008).
These findings further stimulated the investigation of infliximab in
the spondylarthritis concept. It is noteworthy that the first peer
reviewed publication of a successfully treated ankylosing spondylitis
patient with infliximab revealed that this was a Crohn's disease
patient suffering also from ankylosing spondylitis (van den Bosch
et al., 2000). Similarly, the first patient with severe plaque psoriasis
treated with infliximab was also a Crohn's disease patient (Oh et al.,
2000). In these inflammatory bowel disease patients suffering from
concomitant ankylosing spondylitis or psoriasis, infliximab resulted in
improvement of all symptoms, including bowel, spine, and skin.
These clinical findings have encouraged physicians from different
therapeutic fields to consult each other and work more in a cross-
specialty way.
 F. Cornillie / European Journal of Pharmacology 623 (2009) S1–S4
Gastroenterologists were “slow adopters” of infliximab despite the
lack of effective maintenance treatments for Crohn's disease.
Corticosteroids and azathioprine are widely used, and the initial
indication granted for infliximab required severe active Crohn's
disease failing these drugs.
With a careful and successful clinical development program of
infliximab the treatment algorithm of patients with Crohn's disease
and ulcerative colitis is changing slowly.
How did we get there? Infliximab was the first anti-TNF to obtain
market authorization for Crohn's disease in USA (1999) and in USA in
1998 and in EU in 1999. An early compassionate use of infliximab
(2 infusions of 10 mg/kg) in a 12-year old child resulted in quick
symptom relief, and – more surprisingly – in complete mucosal healing
(Derckx et al., 1993). The mucosal healing effect of infliximab was
pronounced and remarkably fast. Mucosal healing was confirmed in a
second small study of 10 Crohn's patients treated with a single infusion
of 10 mg/kg (n = 8) or 20 mg/kg (n = 2). This small study delivered
some key early lessons: first, not all Crohn's disease patients respond to
anti-TNF therapy (7/8 in group 1, and 1/2 in group 2), and second: some
patients will relapse by week 8 after infusion (1/8 in group 1) (van
Dullemen et al., 1995). The mucosal healing effect of infliximab was
confirmed by this small dose-finding and safety study.
Later studies established the effective dose of 5 mg/kg for both
luminal and fistulizing Crohn's disease (Targan et al., 1997; Present
et al., 1999). The effect of single infliximab infusions for the induction
of response and remission was, however, short-lived. Maintenance
studies in both luminal (Hanauer et al., 2002), and fistulizing Crohn's
disease (Sands et al., 2004) were executed successfully. Today,
patients can be treated long-term with infliximab for both Crohn's
disease and ulcerative colitis. The real-life long-term data from the
Leuven inflammatory bowel disease center confirm the clinical
findings of the 10-year long clinical development program of
infliximab in inflammatory bowel disease (Schnitzler et al., 2009).
Today's focus is on optimization of infliximab treatment in
inflammatory bowel disease. Several studies have shown that
scheduled (q8 week) maintenance treatment results in less hospita-
lizations, less surgeries, less resource utilization, and therefore
improved long-term outcomes (Rutgeerts et al., 2004). In addition,
maintenance of adequate infliximab trough levels in treated patients
is beneficial. It's clear that measurable or elevated infliximab trough
levels correlate with clinical response (Maser et al., 2006; Reich et al.,
2005). Synergistic efficacy of some DMARDs (disease modifying anti-
rheumatic drugs) and immunosuppressives like methotrexate and
azathioprine with infliximab may be explained by the longer
maintenance of elevated trough levels with combination therapy.
This was confirmed in Crohn's disease where patients in a 6-month
remission on combination of azathioprine and infliximab were
randomized to either continue or stop azathioprine. Although no
clinical nor endoscopic differences were seen between the 2 groups at
2 years, the patients on continued combination treatment exhibited
higher serum infliximab trough levels and lower CRP levels (van
Assche et al., 2008).
Do we need to measure serum infliximab levels going forward?
Maybe, but more evidence is needed, especially on its predictive value
in individual patients.
1. Where do we go from here?
It needs to be our final ambition to “achieve more” with potent
drugs such as infliximab. Remission in rheumatoid arthritis, remission
without corticosteroids and with mucosal healing in Crohn's disease,
prevention of colectomy in ulcerative colitis, clearance of skin and
nails in psoriasis and psoriatic arthritis are achievable goals with early
treatment, tight control of outcome, and timed change of treatment
strategy.
S3
Improvement of quality of life may largely follow clinical improve-
ment of signs and symptoms and the remission state, but it would
need to become a well defined treatment goal. In addition, parti-
cipation to the work force, i.e. presenteism is now another achievable
goal for patients with chronic inflammatory diseases.
I invite you to enjoy the following contributions on rheumatoid
arthritis by J. Smolen, on inflammatory bowel disease by G. van Assche
et al., and on psoriasis by U. Mrowietz and K. Reich. These well known
experts have made major contributions to the scientific and clinical
development of infliximab during the last decade. Their work has
influenced clinical practice today. Many patients have benefited from
their efforts. That's something to be proud of. They did bring
infliximab “from the bench to the bedside”.
Disclosure
Freddy Cornillie is a full-time employee of Centocor BV.
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