REVIEW

Revolutionary Change in Rheumatoid Arthritis Managementwith Biological Therapy
Tsutomu Takeuchi

Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan(Received for publication on October 5, 2010)(Revised for publication on January 19, 2011)(Accepted for publication on February 17, 2011)

Biological agents targeting a specific molecule have extraordinarily fine specificity and powerful functional capabilities. By the introduction of biological therapy, management of rheumatoid arthritis has
undergone a revolution and a paradigm shift. In this review, I will summarize the role in the pathogenesis of rheumatoid arthritis of the molecules targeted by biological agents. Providing evidence obtainedin clinical trials and investigator-initiated clinical studies in Japan, the effectiveness and safety of biological therapy in rheumatoid arthritis are discussed. Finally, studies aiming at a personalized strategy
with biological agents are listed and the future perspectives toward tailor-made medicine in the field of
rheumatology are discussed. (Keio J Med 60 (3) : 75–81, September 2011)

Keywords: tumor necrosis factor, IL-6, remission, safety

Introduction

Target Molecules in RA

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that results in joint destruction anddisability. Biological agents that target a specific molecule
provide an effective means for therapeutic managementof RA due to their specificity and powerful functional
capabilities, and this approach has resulted in a paradigm
shift in the treatment strategy for this disease. A dramatic
improvement in the signs and symptoms of a patient with
RA was first reported with the chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody infliximab in
1993.1 This observation was confirmed in a double-blind,randomized, controlled study comparing this biologicalagent with a placebo in 1994.2 The first approved biologic
for RA was the TNF receptor IgG1 fusion protein etanercept in the United States in 1998. At present, nine biological agents have been approved for RA worldwide. Thisrevolutionary change in RA management with biologicaltherapeutics in Western countries and Japan3 is reviewed.

Three major cell types (blood vessels, lymphocytes,
and synovial cells) gather prominently in the synovial tissues of patients with RA (Fig. 1). Through interactions
among these cells, pro-inflammatory mediators are released or cells activate each other by direct cell-to-cell
contact, facilitating a lowering of the pain threshold,activation of T and B cells, further proliferation of synovial cells, increased expression of adhesion moleculeson endothelial cells, formation of blood vessels, degradation of cartilage and cartilage matrix, and activation of
osteoclasts among other processes. Of the multiple eventsin the inflamed synovium of RA patients, one of the upstream events, an indispensable factor, was demonstrated
to be the enhanced release of pro-inflammatory cytokines
such as tumor necrosis factor (TNF)-α, interleukin-1, andinterleukin-6. Also, it has been postulated that T and B
cells play important roles in autoimmune-mediated processes for perpetuating inflammation.

Reprint requests to: Tsutomu Takeuchi, MD, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University,
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, E-mail: tsutake@z5.keio.jp
Copyright © 2011 by The Keio Journal of Medicine

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Takeuchi T: Biologics in RA

Fig. 1 Molecular targets in patients with rheumatoid arthritis (RA).
There are several distinctive features of the synovial tissues of patients with RA, including new blood vessel formation, infiltration oflymphocytes, and synovial cell proliferation. Pro-inflammatory cytokines and the molecules involved in the activation of T and B cells
are ideal candidates for molecular targets in RA. VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; APC,
antigen presenting cells; PGs, prostaglandin.

Structure of Biological Agents
With candidate molecular targets in the pathogenesis
of RA identified, much effort has been expended to develop appropriate biological agents. There are two major
types of biological agents: monoclonal antibodies and receptors/ligands fused to the Fc portion of immunoglobulin G (IgG-Fc fusion protein). As shown in Figure 2,
the first monoclonal antibody approved for patients with
RA was chimeric, in which the antigen-binding portionof IgG came from a mouse monoclonal antibody and therest of the molecule from a human antibody, resulting
in about 25% of the protein consisting of mouse aminoacid sequences. These biologics include chimeric monoclonal antibodies against TNFα (infliximab) and CD20
(rituximab). Infliximab was approved in Japan in 2003,
but rituximab has yet to be approved in Japan. Throughdramatic progress in cellular and molecular biology
techniques, humanized and further fully human monoclonal antibodies are being engineered. The humanizedmonoclonal antibody against the IL-6 receptor is tocilizumab, which was developed in Japan and approved for
RA treatment in 2008. A polyethylene glycol-modified
humanized Fab′ fragment against TNFα (certolizumab
pegol) was recently developed and approved in several

countries, though not yet in Japan. Fully monoclonal antibodies against TNFα include adalimumab, which has
been approved since 2005 in several Western countries
and since 2008 in Japan, and golimumab, which has justbeen approved in several countries, though not in Japan. IgG-Fc fusion proteins include the TNFR2-Fc fusion protein etanercept and the CTLA4-Fc fusion protein
abatacept. Etanercept was approved in Japan in 2005 andabatacept was just approved in Japan in 2010. Finally, anaturally occurring regulatory protein designated as an
IL-1 receptor antagonist with some amino acid modifications is anakinra, which has not been approved in Japan.
All of these agents are delivered by either intravenous or
subcutaneous injection.
Mechanism of Action of Anti-TNF Biologics
As shown in Figure 3, three anti-TNF biologics now
available for RA in Japan appear to have different modesof action against TNF. Two monoclonal antibodies, infliximab and adalimumab, can neutralize serum TNFαand inhibit the production of TNFα through lysis orapoptosis of macrophages with membrane-bound TNFα.
In contrast, etanercept can neutralize not only TNFα, butalso another family member, lymphotoxinα. However,Keio J Med 2011; 60 (3): 75–81

77

Fig. 2 Structure of biological agents.
The upper panel shows biological agents generated based on antibody molecules. The lower panel shows those based on the Fc portionof the immunoglobulin-fusion protein, including receptor-Fc fusion protein. PEG, polyethylene glycol; mAB, monoclonal antibody.

it has been reported that etanercept cannot lyse TNFαexpressing macrophages in a complement-dependent
fashion because of the lack of a complement-binding portion in the etanercept molecule.4
Efficacy of Biological Agents in Japanese Patients Q5
Several multi-center, randomized, double-blind clinical
trials of biologics have been conducted in Japan and haveexhibited excellent American College of Rheumatology(ACR) 20 responses in patients, as shown in Figure 3.5–7
In addition, clinical remission achieved in the clinical trials and studies reached about 20–40% of Japanese RA
patients (Fig. 4), implying that clinical remission is a realistic goal of treatment (Table 1). The details for eachbiological agent are discussed below.

a) Infliximab
A series of investigator-initiated clinical studies, including RECONFIRM,8 RECONFIRM-2,9 and RECONFIRM-2 J,10 have demonstrated that a 3-mg/kg doseof infliximab at 0, 2, and 6 weeks, followed by every 8
weeks thereafter, exhibited excellent clinical responses
as well as inhibition of radiographic progression in RA
patients. However, there was a slight dip in the clinical response around 30–38 weeks,9 implying a secondary lossof efficacy with infliximab, which may have been due toinsufficient serum trough levels of infliximab at the subsequent infusion. Previous studies have suggested antibiologics antibodies and/or an infusion reaction to biologics may be the mechanism for insufficient serum levels
or secondary loss of response to biologics. We examined
the anti-biologics antibody and (SNPs) of Fc gamma re-78

Takeuchi T: Biologics in RA

Fig. 3 Efficacy of biological agents in Japanese RA patients.
ACR 20 response data from Japanese clinical trials for each biological agent are shown. The different shaded bars are defined by thedose data. MTX, methotrexate; MTX-IR, MTX-inadequate responder; DMARD-IR, disease-modifying anti-rheumatoid drug/inadequate responder; PL, placebo.

ceptors, demonstrating that FcgR3B high-affinity SNP
NA1/NA1 is significantly associated with infusion reactions, leading to drop out, in addition to anti-biologics
antibody.11 Finally, in the RISING study, 10 mg/kg of infliximab showed a significantly greater clinical responsethan lower doses at 54 weeks with a DAS28 remission of
45% with increased serum trough levels,12 as shown in
Figure 4. Recently, it has been demonstrated that baseline plasma levels of TNFα predict clinical responses toa standard dose of infliximab (3 mg/kg),13 enabling us to
identify in advance RA patients who will require an in-creased dose of infliximab.
b) Etanercept
To determine whether the addition of, or switch to, etanercept is better in MTX-resistant patients, an investigatorinitiated clinical study (JESMR)was started. The results
have demonstrated that the strategy of adding-on showeda significantly higher remission rate, compared to switching, not only at 24 weeks (27% vs. 9%, respectively),14
but also at 52 weeks (35% vs. 18%, respectively).15 In

Table 1 Provisional treatment goals for RA in Japan (2010)
1.

Immediate clinical remission inductiona)and its maintenance.

2. Halting progression of structural damageb)(structural remission).
3.

In early disease, functional remissionc)should be the aim to achieve complete remission ultimately.d)4.

After achieving clinical remission for 12-24 months, biologics-free and drug-free remission should be considered.

a) Clinical remission: DAS28(ESR)<2.6 or DAS28(CRP)<2.3b) Halting progression of structural damage: no new erosion and JSN on X-rayc) Functional remission: HAQ-DI ≤0.5, or J-HAQ ≤0.5d) Complete remission: satisfy all of 1 to 3
MHLW study group『Study on systematization of remission induction in RA』

Keio J Med 2011; 60 (3): 75–81

79

Fig. 4 Clinical remission in Japanese RA patients treated with each biological agent.
The figure shows the percentage of RA patients achieving clinical remission. IFX: infliximab; ETN: etanercept; TCZ: tocilizumab.
Duration of the study is shown in parentheses. *Clinical remission was judged by DAS28-CRP. #Clinical remission was judged by
DAS28-ESR.

addition, erosion scores after a 52-week treatment weresignificantly lower in patients with etanercept + MTX
compared to those who switched from MTX to etanercept alone. These results indicate that etanercept should
be added on to MTX in MTX-resistant RA patients when
etanercept is started.
c) Adalimumab
It is interesting to note the higher incidence of antiadalimumab antibody development (40.2%, 44.0%,
and 26.4% at 24 weeks for doses of 20 mg, 40 mg, and80 mg every 2 weeks, respectively, in Japan, compared
to 15–20% for a 40 mg dose in Western countries) in an
adalimumab monotherapy trial.7 This may have been thecause of the lower response rates to doses of 20 mg every
2 weeks, and implies that different genetic backgrounds
affect the production of anti-biologic antibodies.
d) Tocilizumab
Tocilizumab, a humanized monoclonal antibody
against the IL-6 receptor, was first approved in 2008 for
RA treatment in Japan, followed by approval in Europe
and the USA. The excellent efficacy and safety of tocilizumab monotherapy has been demonstrated in Japanesepatients.6,16 The effectiveness of tocilizumab in dailyclinical practice was also confirmed in the Reaction
study, which found a high remission rate at 24 weeks17and 52 weeks18 (Fig. 4).
e) Effect on structural damage
In the SAMURAI trial,19 not only the total Sharp score(TSS), but also the erosion and joint narrowing scores
were significantly lower in tocilizumab monotherapy
compared to disease-modifying anti-rheumatoid drug
(DMARD) therapy, showing the first evidence that biologics are superior to DMARDs in Japanese patients forinhibiting structural damage. Subsequent clinical trials
and studies of infliximab12 revealed a striking inhibitionof structural damage when compared to those reported
from studies in Western countries,20 and these trials generated interest for examining the effect of tocilizumab +MTX combination therapy on joint damage over tocilizumab therapy alone in Japanese RA patients.
Safety of Biological Agents in Japanese Patients
For close monitoring of adverse events associated withbiologics, and to confirm their effectiveness, post-marketing surveillance (PMS) of all RA patients who havereceived biologics has been conducted in Japan. The
primary objectives of PMS are to determine the exact

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Takeuchi T: Biologics in RA

frequency of drug-related adverse events, particularly related to opportunistic infections such as tuberculosis, andthe factors affecting drug safety and efficacy. To date,
PMS for infliximab and etanercept has been completed
and reported,21,22 showing that adverse drug reactions(ADRs) for infliximab and etanercept were observed in
28.0% and 30.6% of patients, respectively, and severe
ADRs were observed in 6.2% and 4.6% of patients, respectively. When compared to those patients treated withthe oral DMARD tacrolimus (results of a company-initiated PMS for 24 weeks: n =3175, ADR =36.0%, severe
ADR = 6.4%),23 incidences of ADRs and severe ADRs
in infliximab and etanercept were comparable, indicating that biologics are tolerated by Japanese RA patients.
Of the severe ADRs, pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia (PJP) were found to be important.3 In particular, PJP is an important opportunistic
infection in acquired immunodeficiency syndrome, but
the exact incidence of PJP in RA patients treated with
TNF inhibitors is not well known. Japanese PMS for infliximab first demonstrated that the incidence of PJP in
5000 patients treated with infliximab was 0.4%,21 which
is more than ten times higher than the self-reported incidences in Western countries. It is interesting to note thatthe clinical features and radiographic patterns for PJP in
RA patients receiving infliximab appear to differ fromthose of patients with human immunodeficiency virus
infections.24 During PMS for etanercept, PJP developedin 0.2% of the patients, and 6 of these 25 patients died,raising concern for PJP in TNF blockade and highlighting the need for prophylaxis against patients at risk withsulfamethoxazole-trimethoprim (ST) compounds. In thisregard, serum beta-d glucan was anticipated to be usefulfor the diagnosis and monitoring of PJP development,25
and this was confirmed in RA patients.3
Future Perspectives for Biological Agentsin RA Treatment
When utilizing a number of powerful tools such as biological agents to manage RA, a personalized strategy ofRA treatment is required. For example, it has been shownthat infliximab can be stopped in early RA after achieving low disease activity or remission.26,27 To test whether
this is the case for established RA, investigators initiated a clinical study.28 Among 102 patients who could be
evaluated, around half of the patients had successfully
discontinued infliximab after 1 year. Among those, 67%of the patients showed no radiographic progression.28 For
a treatment strategy with tight control while utilizing biologics, with the goal of clinical remission or low diseaseactivity, a discontinuation of the biologics may be possible for some patients. This strategy is now being examined in Japanese patients for several biologics, including
infliximab, etanercept, tocilizumab, and abatacept.
In order to identify predictive factors for a given bio-

logical agent, genetic polymorphism29,30 and comprehensive mRNA expression analysis31,32 have been employed.
Following this line, many investigators are extensively
searching for predictive factors of ADRs, including infection33 and infusion reactions of biologics.11
Conclusion
Experiences with biologics in Japan show a greater efficacy than those in Western countries, but several important side effects such as opportunistic infections withsome increased incidence underline the risks of biologics.3 We should pay much more attention to the variables
in RA patients, and we need to maximize the efficacy andminimize the risk of biologics in individual RA patients.
In addition to clinical information for the personalizationof biologic treatments, research to identify predictors of
the responses to, and the risks of, biologics is required.
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