Anti-TNF Biological Agents inRheumatoid Arthritis and OtherInflammatory DiseasesTsutomu Takeuchi1, Kouichi Amano1, Hideto Kameda1 and Toru Abe2

ABSTRACTIt is now evident that biological agents targeting on the tumor necrosis factor (TNF) have not only induce a sub-stantial clinical response, but also inhibit the structural damage in patients with Rheumatoid Arthritis (RA). Uponthe great success of anti-TNF biologicals as the therapeutic modalities of choice in the treatment of inflamma-tory disorders of unknown etiology, the details of TNF, and anti-TNF biological agents are extensively reviewed,particularly, focusing on those used against RA. So far, nearly one million patients are expected to expose tothese agents worldwide. In Japan, chimeric monoclonal antibody to TNFα, infliximab has been approved forCrohn’s disease in 2002, RA in 2003, and TNF receptor 2-IgG Fc fusion protein, etanercept had just approvedfor RA in 2005. Full human anti-TNFα monoclonal antibody, adalimumab is now under clinical trials. Safety pro-files of these agents, based on the exposure to one hundred million patients for up to ten years, are summa-rized. While the experiences using biological agents in Japan are rather limited, the unique circumstances inAsian countries should been taken into account. In this respect, the issues around the anti-TNF biologicals inJapan are finally discussed.

KEY WORDSMonoclonal antibody, RA, Receptor antagonist, TNF

INTRODUCTIONTumor necrosis factor (TNF) was first isolated in1975, as a factor with the potential to kill tumor celllines in vitro.1 In addition, two other factors with simi-lar physiological activity were identified, and desig-nated as lymphotoxin α and β (LT-a, LT-b).2-4 TNFsare believed to play an important role in host defenseagainst infections and tumor development . 4,5 How-ever, accumulating evidence has suggested that over-production of TNFs is closely related to the patho-genesis of inflammatory disorders such as rheuma-toid arthritis (RA), Crohn’s disease, and other inflam-matory diseases . 6,7 Subsequently , much effort hasgone into the development of therapeutic agents ,which target TNFs. These efforts have resulted inanti-TNF biological agents , which have shown dra-matic improved outcomes in RA patients as well as inpatients suffering from other inflammatory disorders

of unknown etiology . 8,9 These biological agents ,which directly target the inflammatory cytokineshave revolutionized our strategy in the managementof such diseases.10

ACTION AND STRUCTURE OF TNFαTNF binds to specific TNF receptors ubiquitously ex-pressed on the surface of cells throughout the body,and has a long list of physiological actions.4,5 An ex-cess amount of TNFα in the serum can alter the anti-coagulant activity of the endothelial cells and rewul inthe induction of hemorrhage, vasodilatation, and neu-trophil activation , all prominent features of septicshock. On the other hand, a small but significant in-crease in the long term concenration of TNFα mayevoke inflammatory responses, such as fever , ane-mia, body weight loss , and even osteoclast activa-tion.7Among tumor necrosis factors, TNFα and TNFβ

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REVIEW ARTICLE

1Division of Rheumatology, Saitama Medical Center , SaitamaMedical School, Saitama, Japan. 2Emeritus Professor , SaitamaMedical School.Correspondence: Tsutomu Takeuchi, Division of Rheumatology,Saitama Medical Center, Saitama Medical School, 1981 Tsujido-

machi, Kamoda, Kawagoe, Saitama 350−8550, JAPAN.Email: tsutake@saitama−med.ac.jpReceived 5 March 2004.�2005 Japanese Society of Allergology

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Table 1 Biological agents targeted on tumor necrosis factor

antibody mouse human PEG

PEG-TNFαFabCDP870

full human anti-TNFαadalimumab

humanized anti-TNFαCDP571

chiemric anti-TNFαinfliximab

receptor: Fc fusion protein TNFR human IgG Fc PEG

PEG-TNFR Ⅰ: FcTNFR Ⅰ: Fclenercept

TNFR Ⅱ: Fcetanercept

Table 2 Approval status of anti-TNF biological agents

・infliximab　Crohn’ s disease : 98 USA, 98 EU, 02 JAPAN

　RA : 99 USA, 00 EU, 03 JAPAN

　Ankylosing spondylitis : 03 EU

・etanercept

　RA : 98 USA, 00 EU, 05 JAPAN

　JIA : 99 USA, 00 EU

　Psoriatic arthritis : 02 USA

　Ankylosing spondylitis : 03 USA, 03EU

・adalimumab

　RA : 02 USA

(a.k.a : lymphotoxinα), and lymphotoxin β have beenpreviously identified . 4 These three molecules aregenerated from three distinct genes on the chromo-some 3 and act as trimers , binding to receptors ,which also consist of homotrimers.5 TNFα consists ofhomotrimers of TNFα, TNFβ consists of homotrim-ers of TNFβ (LTα), and lymphotoxinB is a combinedfrom of LT-α and LT-β1. TNFα and TNFβ can bind totwo kinds of TNF receptors, namely TNF receptor I(p55) and TNF receptor II (p75). The unique het-erotrimers, consisting of two molecules of LT-α andone molecule of LT-β binds to the third receptor, des-ignated as LT-βR. It has long been thought that eachof the receptor molecules exists independently, andassemble during ligand binding. This model is knownas the “ ligand-induced trimerization” model . Sincesignal transduction occurs independently, dependingon the individual class of receptor,11 it is widely ac-cepted that a single receptor is primarily assembled

as a trimer. This pre-ligand assembly model is nowrecognized as the correct process since a pre-ligandassembly domain (PLAD) has been identified.12The majority of TNFα is produced by a variety of

cells including monocytes�macrophages, T cells, Bcells, and keratinocytes.5 Upon stimulation, signalsare transduced from the cell surface receptors intothe cytoplasm,11 ultimately leading to activation of thetranscription factors and binding of the promoter re-gion of the targeted genes which initiates final tran-scription of TNFα. Regulation of the stability of themessenger RNA (mRNA) for TNFα is controlled bystabilizing factors and destabilizing factors , whichbind the AU-rich region located within the 3’ untrans-lated region (UTR) of mRNA. One of the stabilizingfactors is HuR, while TIA-1 acts as a destabilizing fac-tor. Thus TNFα is produced with the transmembranedomain is transported to the surface of the cell mem-brane, and expressed on the cell surface. When mem-brane proteases such as TNF-α Converting Enzyme(TACE) are activated in pathological conditions orMT-MMP in physiological conditions cleave TNF-αon the cell surface, the end result is the release offree TNF-α.5

ROLE OF TNF-α IN THE PATHOGENESIS OFRAEarly experiments have demonstrated that RAsynovial cells produced an excess amount of TNF-αin vitro, and anti-TNF-α monoclonal antibody inhib-ited not only TNF-α, but also subsequent productionof IL-1, IL-6, and IL-8. These findings suggest thatTNF-α is located upstream of the cytokine cascade.6,7

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Fig. 1 Action of anti-TNF biological agents

TNF α

Target cells

TNFRⅠ(p55)

caspase NFκB

Pro-innflammatory cytokine gene

Apoptosis

fibroblastMonocytes/macrophages

Cytoplasmicmembranes

etanerceptetanerceptinfliximabinfliximab

InflammationInflammation

mTNF α

adalimumabadalimumab

TNF β

TNFRⅡ(p75)

lymphocytes

To test the hypothesis that TNF-α plays a pivotal rolein RA pathogenesis, TNF-α transgenic (tg) mice weregenerated. Results showed that erosive polyarticulararthritis developed in the TNF-α tg-mice, and block-ade of TNF-α significantly reduced both the severityand even the development of arthritis, in addition toassociated structural damage . Furthermore , it wasdemonstrated that the anti-TNF-α monoclonal anti-body could ameliorate a collagen-induced type of ar-thritis . These results have provided evidence for aTNF blockade strategy, which has facilitated the de-velopment of a clinical application of this approach inthe management of inflammatory arthritis.13

BIOLOGICAL AGENTS INHIBITING THE AC-TIVITY OF TNF-αSeveral strategies for the production of biologicalagents, designed to inhibit the activity of TNF-α havebeen adopted . There are two major categories ofsuch agents : one is a monoclonal antibody, and an-other is a receptor-antagonist�receptor-Fc fusion pro-tein . Table 1 show the monoclonal antibodies suchas , the chimeric monoclonal antibodies to TNF-α(clone cA2, inflixiamab : Remicade�),14 humanizedmAb (CDP571) , 15 full human mAb (clone D2E7,adalimumab : Humira�),16 and the polyethylene gly-col (PEG)-Fab fragment (CDP870). Receptor antago-nist�receptor-Fc fusion proteins-include, the TNF re-ceptor II-Fc fusion protein (etanercept : Enbrel�) ,the TNF receptor I-Fc fusion protein (lenercept), andthe PEG-TNF receptor I.17 Infliximab, adalimumab,and etanercept have been approved for clinical use inthe United States. Table 2 shows the approval statusof these products worldwide . The first biologicalagents approved for the treatment of RA was etaner-cept in 1998, followed by infliximab in 1999 in the

United States of America. In the year 2002, infliximabwas approved for induction into the Japanese marketfor the treatment of Crohn’s disease, followed by ap-proval for treatment of RA in 2003.The indications of for use of etanercept include RA,JIA,18,19 psoriatic arthritis,20 and ankylosing spondyli-tis,21,22 whereas those for infliximab are RA, Crohn’sdisease,23,24 psoriatic arthritis,25 and ankylosing spon-dylitis.26-28

EFFICACY OF THE BIOLOGICAL AGENTSInfliximab : This chimeric mAb consists of a variableregion of mouse immunoglobulin (Ig), which binds toTNF-α with high affinity (Ka = 1.8 × 109), and the Fcportion of human IgG1 (Table 1 & Fig. 1)．

SINGLE INFUSION TRIALThe first clinical trial of infliximab was carried out insevere RA patients who had not responded to conven-tional DMARDs. In this study a single infusion at 5―20 mg�kg clearly showed a striking improvement inthe reduction of signs and symptoms.14 Due to thegradual decrease in the serum concentration of in-fliximab and total disappearance at 3―4 weeks post-infusion , the disease activity returned to the pre-treatment level , suggesting that repeated infusionsare required to control long-term disease activity．

REPEATED INFUSION WITHOUT MTXClinical trials with repeated infusions of infliximab inRA patients has demonstrated that the intervals be-tween infusions became shorter when infusions wererepeated more than several times . 29 It is assumedthat the development of the human antibody to chi-meric monoclonal antibody (HACA) was interferingwith the infliximab activity,30 thereby shortening the

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Fig. 2 Clinical response of anti-TNF biological agents (ACR responding rate)

20

5

0

23

911

5

33

30

19

8

2

30

10

3

52

28

12

6159

40

4

60

39

15

53

35

8

63

39

21

70

60

50

40

30

20

10

0

placebo

infliximab

1

placebo 20 5 23 9 5 33 3 19 2 30 10

infliximab 52 28 12 35 59 40 60 39 53 35 8 63 39 21

ACR20 ACR50 ACR70 ACR20 ACR50 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

infliximab(MTX) infliximab (JAPAN) etanercept (MONO) etanercept (MTX) adalimumab (MONO) adalimumab(MTX)

61

11 1 8

4 15

0 0 3

35

intervals of the infusion to maintain the efficacy.

DOSE RANGING STUDY WITH OR WITHOUTMTXExciting clinical evidence by Maini et al. has shownthat low doses of infliximab such as 1 or 3 mg�kg incombination with MTX showed a clinical responsecomparable with that of high doses of infliximab (10mg�kg) alone . 31 The dose sparing effect of MTXcould be attributed to immunosuppression of HACAproduction. Indeed, in the MTX�infliximab combina-tion therapy, the frequency of HACA detected in theserum of the patients was significantly lower than inthose patients treated with infliximab alone.

COMPARISON STUDY BETWEEN MTX ALONEAND MTX+INFLIXIMAB (ATTRACT)To prove the efficacy of infliximab and MTX combina-tion therapy, the Anti-Tumor Necrosis Factor Trial inRheumatoid Arthritis Concomitant Therapy ( AT-TRACT) study was conducted in 428 patients with se-vere RA, who did not respond to MTX with a dose ofmore than 12. 5 mg�week.32 After 54 weeks, the pa-tients treated with MTX+Placebo infusion showedonly a 17% response, whereas all of the infliximab

treated group showed a significant response, 56% ofthe patients achieving the ACR 20% response(Fig. 2 ) . 33 Surprisingly , the mean change in themodified sharp score , which represents the semi-quantitative measure of bone and cartilage destruc-tion, showed more than 7 in the placebo group (onlyMTX), while it was markedly suppressed to less than1 in all the infliximab treated groups.33 These resultssuggest that infliximab in combination with MTX notonly reduces the signs and symptoms of RA, but alsostrongly inhibits the radiographic progression ofstructural damage.32,33

JAPANESE TRIALIn Japan, a clinical trail with a similar design was car-ried out in three groups with MTX + placebo, MTX +infliximab (3 mg�kg), and MTX + infliximab (10 mg�kg) at 0, 2, and 6 weeks, and demonstrated a signifi-cantly better clinical response in the infliximabtreated group. The ratio of patients treated with in-fliximab 3 mg�kg to the ACR20% responding criteriawas 61% at 14 weeks.34 When the Japanese trial datawas compared to the results observed in the AT-TRACT study, the Japanese trial exhibited a slightlybetter result (∆ACR 20% [{that in MTX + infliximab} −

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{that in MTX placebo}]) at week 14 : 34% in the Japa-nese trial vs the ATTRACT study. One of the majordistinctions between Western countries and Japan isthe maximum dosage of MTX, which is 8 mg�weekin Japan, raising the possibility that Japanese RA pa-tients with a lower maximum doses of MTX wouldhave milder disease activity than their Western coun-terparts, and thus demonstrating a better response toinfliximab.

COMPARISON OF MTX + PLACEBO, AND MTX +INFLIXIMAB IN EARLY RAMTX alone or two doses of infliximab (3 mg�kg, or 6mg�kg ) with MTX were compared in early active RA(less than 3 years after onset of RA) with poor prog-nostic factors . After 54 weeks , the combination ofMTX and infliximab at any doses exhibited a signifi-cantly high ACR 20, 50, and 70% response, as well asa significantly smaller increases in the total sharpscore, indicating that the effect of the combinationtherapy on early active RA is superior to that of MTXalone . The numbers of total and severe adverseevents were comparable among the three treatmentgroups , supporting the idea that the combinationtherapy should be considered in the treatment ofearly active RA with a poor prognosis, where the ra-diographic structural damage is progressing rapidly,leading to a profound irreversible disability.35Etanercept : Etanercept is a genetically engineered

protein consisting of two molecules of the extracellu-lar domain of TNF receptor II (p75) and Fc fragmentof IgG1 (Fig. 1 & Table 1).

DOSE RANGING STUDYIn an earlier study, the effects of placebo and etaner-cept 0.25 mg�m2, 2 mg�m2, and 16 mg�m2 were com-pared in 180 RA patients, who had demonstrated alack of efficacy to therapy with between one and fourof the previous DMARDs. After 3 months of treat-ment, a significant reduction of disease activity wasobserved in the etanercept treated-group, and dose-related therapeutic effects were confirmed . In RAtreated with 16 mg�m2 of etanercept, 75% of the pa-tients achieved the 20%ACR response, whereas theplacebo group produced only 14% response.36

PLACEBO-CONTROLLED TRAIL (PLACEBO, 10MG, 25 MG)Thereafter, a randomized placebo-controlled trail us-ing fixed etanercept doses such as 10 mg and 25 mgtwice a week for 24 weeks was designed and carriedout in 234 patients with active RA for 6 months. Re-sults showed a profound reduction of all the core setvariables in the etanercept group, and the 20%ACR re-sponse was 59% in the etanercept treated-group (25mg twice a week), and only 11% in the placebo group(Fig. 2).37

ADD-ON STUDY TO MTXA further study was carried out to examine the effi-cacy of Etanercept in patients with inadequate re-sponse to a stable dose of MTX. In the group treatedwith etanercept 25 mg twice a week, the 20%ACR re-sponse rate was 71%, while placebo produced a 27%response, indicating that etanercept is also exhibitinga significant benefit in RA with MTX inadequate re-sponders (Fig. 2).38 The follow up studies showed asustained clinical response for up to three years.39

COMPARISON OF MTX AND ETANERCEPT INEARLY RATo test the efficacy of etanercept in early RA, a directcomparison between etanercept and MTX was car-ried out in 632 patients, diagnosed as having RA forno more than 3 years and no prior treatment withMTX.40 The patients were divided into three groupsconsisting of MTX (n = 217), 10 mg etanercept (n =208) , and 25 mg etanercept (n = 207 ) . MTX wasstarted with a weekly dose of 7.5 mg, followed by anincrease up to 15 mg�w at week 4, and 20 mg�w atweek 8 with folic acid supplementation (1 mg�day).After the second dose escalation, the mean dose ofMTX was only 19 mg�week, because 15% of the pa-tients needed to reduce the dose due to adverseevents. After 24 weeks, patients treated with 25 mg ofetanercept showed a more rapid improvement, moreACR20% , 50% , and 70% response rates over MTXtreated patients . 40 Radiographic evaluation revealedthat the mean increase in the erosion score was 0.30in patients treated with 25 mg of etanercept, and 0.68in MTX group , whereas joint-space-narrowing wascomparable between the two groups.40 A two year fol-low up study demonstrated that the mean changes inthe total sharp score in the 25 mg etanercept groupwere significantly lower than those in the MTX group(1.3 and 3.2, respectively), suggesting that etanerceptacted more rapidly to reduce the clinical parameters,and retard joint damage in early active RA.41

COMPARISON OF MTX , ETANERCEPT , ANDMTX + ETANERCEPT IN EARLY RA ( TEMPOSTUDY)In 682 early active RA (less than 3 years), patientstreated with MTX+etanecept showed a significanthigh ACR70% response and a high clinical remissionrate according to the DAS definition, in addition to asignificantly low mean sharp score below zero, com-pared with the groups on MTX and etanercept alone.These remarkable results indicate that the combina-tion can achieve remission in a much higher propor-tion in early active RA patients with a poor prognosticprofile than MTX alone or even etanercept alone, andfurthermore it may arrest or even repair the struc-tural damage.42Adalimumab : Adamimumab is a full human mono-clonal antibody of IgG1, which binds to TNF-α with

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Table 3 Incidence of tuberculosis in patients with anti-TNF biologicals62

AdalimumabEtanerceptInfliximab

2,500 150,000 200,000 number of pts

4900 pts・yr230,000 pts・yr230,000 pts・yrpts・year

13 38 172 number of Tb

60%90%64%USAareas used

40%10%36%non-USA

3 20 55 USAareas developed

10 18 117 non-USA

3―8 month1―22 months（Median

11.2）75%: within 6 week97%: within 7 month

onset after infusion

40%50%45%extra-pulmonary/miliary

high affinity (Kd = 6 × 10−10M). The antibody with theclone name of D2E7 is made by the phage displaymethod with amino acid sequencing from the humangermline (Table 1 & Fig. 1)．

COMPARISON OF PLACEBO AND SEVERALDOSAGES OF ADALIMUMABTwo hundred and eighty-four active RA patients, whohad not responded to DMARDs, were randomly as-signed to receive weekly subcutaneous injections ofadalimumab (20 mg, 40 mg, or 80 mg) or placebowithout concomitant DMARDs for 12 weeks .Adalimumab significantly improved the signs andsymptoms of RA with significant better ACR20% re-sponse rates (20, 40, 80 mg for 50.7% , 57.1% , and54.2%, respectively, versus 10.0% for placebo)16 (Fig.2)．

MTX ADD-ON TRIAL (ARMADA STUDY)Two hundred and seventy-one active RA patientswere randomly assigned to four treatment arms ofplacebo + MTX, 20 mg, 40 mg, and 80 mg of adlimu-mab every other week over 24 weeks.43 The patientswere active even though a sufficient dose of MTX(12.5―25 mg�w or 10 mg if intolerant to higherdoses) was administrated for at least 6 months. All ofthe adalimumab treated groups showed a signifi-cantly higher ACR20% and 50% response rate thanthat in the placebo group (Fig. 2).43 Furthermore, theACR70% rate in the 40 mg and 80 mg groups was sig-nificantly higher than in the placebo group. These re-sults suggest a rapid and sustained improvementover 24 weeks compared with MTX alone, althoughthe effect on radiographic progression was not docu-mented in this trial.Summary of the three anti-TNF biologics (Fig. 2) :

The efficacy of the above three agents in the ad-vanced RA patients who have had an inadequate re-sponse to MTX appears to be comparable , demon-strating approximately 60% of ACR20, 40% of ACR50,and 20% of ACR70.44 As illustrated in the 2002 updateversion of the ACR guideline for the management ofRA, the biological agents are now positioned as an-

chor drugs.45 Based on these results in early activeRA patients, evolving evidence of dramatic efficacy,which could pave the way for a hypothesis for the useof combination of biologic agents with MTX directedat arresting the disease in the early course RA pa-tients with a poor prognostic profile, is within the win-dow of opportunity in the foreseeable future.46

SAFETYGenerally, biological agents are well tolerated, andsafe in most patients. Frequent, but less severe sideeffects with standard management have been re-ported . While infliximab has been used in over500,000 patients and etanercept in 200,000 patientsworldwide, few, but severe adverse events have accu-mulated. The individual events are listed as follows.

INFUSION�INJECTION REACTIONSInfliximab has been associated with infusion reac-tions , which are rare severe events such as life-threatening anaphylaxis reactions . The lower thedose of MTX or infliximab, the higher the rate ofHACA production.47 In previous studies in Westerncountries, the minimum dose of MTX against HACAproduction was 7.5 mg�week and that of infliximabwas 3 mg�kg. In clinical trails in Western countries,the frequency of infusion reactions has been reportedto be around 5%48 while that of placebo infusion was2.0%. The patients with infusion reactions leading towithdrawal accounted for 2.5%, and those with seri-ous infusion reactions were 0.8―3%. In Western coun-tries at a does of more than 7.5 mg�week, HACA canbe detected in up to 10% even with the concomitantusage of MTX. There was a concern that the fre-quency of infusion reaction and HACA productionwould be higher in Japan, since the average dose ofMTX used in Japan has been much lower than that inWestern countries. However, the frequency of infu-sion reaction and HACA production was comparablebetween Western countries and Japan , suggestingthat the minimum weekly MTX dose of 6 mg in theJapanese clinical trial would have an immunosuppres-sant effect similar to those doses used in Western

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・Rheumatic diseases　　polymyositis/dermatomyositis, systemic sclerosis, systemic lupus erythematosus98

　　polumyalgia rheumatica91, adult still’ s disease92

Wegener’ s granulomatosis82―84, giant cell arteritis 86, 87, systemic vasculitis85

・Inflammatory diseases

　　Behcet’ s disease, secondary amyloidosis90, ul-cerative colitis93

・Immunological diseases

　　graft versus host disease94

・Granulomatous diseases

　　saocoidosis88, 89

・Hematologic diseases

　　myelodysplastic syndrome95, multiple myeloma96

・Fibrotic diseases

　　interstitial pneumotitis97

Table 4 Possible targets by anti-TNF biological agents

countries.On the other hand, injections of etanercept may

lead to local reactions, reportedly in 40―45% of pa-tients.49 The reactions have usually been mild, andmost of them appear to resolve spontaneously or withappropriate management such as rotation of the injec-tion site or anti-histamines. It has been shown thatanti-neutralizing antibodies have never been devel-oped , although anti-etanercept antibodies could bedetected to some extent．It is interesting to note that human anti-human anti-

bodies (HAHA) or anti-idiotypic antibodies could bedetected in patients treated with adalimumab, and thefrequency appears to be 1―12%. Furthermore, anti-neutralizing antibodies have been observed with afrequency of around 5% , in spite of the fact thatadalimumab is a full human genetically engineeredproduct. Concomitant use of MTX should reduce thefrequency, as in the case of infliximab．

INFECTIONSA series of basic experiments have indicated thatblockade of TNF-α results in serious infectious dis-eases caused by intra-cellular pathogens such as My-cobacterium, 50-53 Pneumocystis carinii 54 and otherfungi,55 legionella,56,57 and Listeria monocytogenesis.58In the ATTRACT study, the frequency of infection

was 40% in MTX used alone, while it was 50% in theMTX + infliximab combination group, with no statisti-cally significant difference.59 The frequency of seri-ous infection between patients treated with MTXalone and that with MTX + infliximab was almost thesame. Similarly, the rate of infection in etanercept-treated patients was 50―60%, which was similar tothose in the control population.59 Again, the risk forserious infection was comparable between the gen-

eral population and etanercept treated patients. How-ever , the incidence of severe infections in patientstreated with anti-TNF biologicals in the clinical set-ting, though not clinical trials, has been reported tobe high with less signs and symptoms.60Mycobacte-rium tuberculosis had been reported in three patientsin major clinical trials including ATTRACT, ACCENT,and PROMPT.However , a post-marketing survey revealed thatthe incidence of tuberculosis would be high in RA pa-tients treated with MTX + infliximab, particularly inEurope . 61,62 Until August 23, 2002, 277 cases hadbeen reported to the FDA63Arthritis, # 132 Arthritis. , # 132,while infliximab was used in 365,201 with the relativerisk of around 7% in the general population .64Seventy-five percent of these patients developed tu-berculosis within the first 6 weeks (3 infusions), andthe incidence was higher in endemic regions, sug-gesting that its appearance was due to reactivation oflatent tuberculosis. 64 Although the incidence of tu-berculosis in RA patients treated with etanercept ap-peared to be at the upper limit of the normal con-trols.65 It is reported that the risk can be seen in pa-tients treated with adalimumab (Table 3). Since in-fliximab and adalimumab are believed to lyse TNF-expressing macrophages (Fig. 1), which play an in-dispensable role in host defense against Mycobacte-rium infection,64 the incidence may be higher in pa-tients treated with infliximab and adalimumab. Giventhe observation that the onset is 11 months afterstarting etanercept, we need to pay close attention tothe incidence of tuberculosis in the long-term treat-ment of patients treated with all of the biologicalagents including etanercept. Considering the relativehigh risk for tuberculosis, the PPD skin test has beenrecommended to rule out latent tuberculosis infec-tion.64,65 Following implementation of this screening,the incidence of tuberculosis in patients being treatedwith anti-TNF biologicals was reportedly even lowerthan in prior studies.62 Given the high incidence of tu-berculosis in Japan, with 30 out of 100,000 in 2001,which is one of the highest among most of the indus-trialized nations, where it is less than 10�100,000, itcan be assumed that the estimated increased risk oftuberculosis in Japan is up to 7 × 30�100,000. In thisrespect, guidelines for the prescription of infliximabin Japan have been proposed by the study group ofMinistry of , health , labor , and welfare (MHLW)at2003.66 (Table 5), and have been used in Japan for apost-marketing survey of all RA cases. Six cases of tu-berculosis have been reported in the initial one thou-sand cases for six months observation.67 In addition,six cases of Pneumocystis carinii pneumonia were re-ported . Although those patients were treated withsuccessful resolution of the condition, we need to payattention to other opportunistic infections such asthose caused by fungi including P. carinii 68 in addi-tion to mycobacterial infection, and look at the simi-

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Table 5 Japanese Guidelines for the use of infliximab of RA proposed by study group of RA, MHLW.

Indications:Active RA despite previous treatment with MTX (Rheumatlex)(≥3 months with MTX ≥6 mg/w). The following 3 items are satisfied.

1. ≥6 painful joints

2. ≥6 swollen joints

3. CRP ≥20 mg/L or ESR ≥28 mm/hr

As a patient who has low risk of opportunistic infections. The following 3 items should be satisfied.

1. WBC, ≥4000/mm3

2. Total lymphocyte count, ≥1000/mm3

3. β-D-glucan negative

Contraindications:

1. Active infectious disease

2. History of a serious infection during the past 6 months

3. Chest X-rays showing old TB (e.g. Calcification shade ≥5 mm) 4. Latent TB. When the cases where benefit outweigh risks, medication of Remicade is considered after treatment of TB.

5. History of ex-pulmonary TB, Carinii pneumonia

6. Congestive heart failure

7. Malignant tumor, demyelinative disease

Cautions:

A. Following items are important, because for screening of Infection (TB, opportunistic infections) and side effects.

1. Chest X-rays can be taken within the same day. And it can be read by Pulmonologist or Radiologist.

2. Opportunistic infective disease can be treated.Evaluate risk through an interview, tuberculin test, chest X-ray, and chest CT scan etc.

B. The caution and preparation for an infusion reaction (including anaphylactic reactions) is required.

The institution which can carry out an emergency treatment: Keep air-way, Oxygen, Epinephrine, Corticosteroids, etc.

larities and dissimilarities of the opportunistic infec-tions between Western countries and Japan.

AUTOIMMUNITYIt has been reported that infliximab and etanerceptcan induce production of anti-nuclear antibodies andanti-DNA antibodies , although the titer of the anti-bodies remains low.69,70 In the earlier studies, the in-creased risk for developing SLE had been seriouslyconsidered. However , the incidence of the diseasehas not been significantly elevated in the treatmentgroup and it is not a severe life-threatening diseaseeven if it does develop.71-74 On the other hand, therisk for demyelinating diseases such as multiple scle-rosis and optic neuritis75,76 appears to be high, andTNF blockade therapy is contra-indicated in patientswith these diseases. Curiously, a recent clinical trialon the chronic inflammatory demyelinating diseasessuggests a significant positive clinical response . 77The changed cytokine environment, which is largelyskewed by anti-TNF biologicals , is believed to ac-count for the change in the profile of autoantibodyproduction and the phenotype of the autoimmune dis-eases．

MALIGNACIESAs mentioned above, TNF-α has been identified as afactor inducing tumor cell lysis in vitro. Thus, onemay wonder whether a blockade of TNF-α would re-sult in an increase in the incidence of malignancy. Sofar the incidence of non-hematological malignancieshas been demonstrated to be comparable with thegeneral population , while that of malignant lym-phoma may be higher in patients treated with anti-TNF biologicals.78 Agent due to evidence that the in-cidence is higher in RA, more active disease , andMTX users, the risk is not simply attributed to bio-logical agentes alone. We still need to follow up theincidence carefully over an extended period.

CONGESTIVE HEART DISEASESSince it has been proposed that TNF-α has a role inthe pathogenesis of heart failure, clinical trials of in-fliximab and etanercept have been conducted for pa-tients with congestive heart failure.79 In contrast tothe earlier expectation, the mortality rate in patientsusing higher amounts of infliximab has become evi-dently higher than that of the placebo group,79 and nosignificant benefit was reported in the etnaercept

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treatment group.80,81 These results indicate that anti-TNF biological agents are not appropriate for the pa-tients with congestive heart failure．

ANTI-TNF THERAPY IN OTHER DISEASES(TABLE 4)Following the great success of anti-TNF biologicalagents as the therapeutic modalities of choice in thetreatment of inflammatory disorders of unknown eti-ology, their possible application in the treatment ofother diseases is now being explored, including in along list of diseases such as Wegener’s granulomato-sis82-84 and other types of vasculitis,85-87 sarcoidosis,88,89 amyloidosis , 90 polymyalgia rheumatica , 91 adultStill’s disease,92 ulcerative colitis93 graft vs host dis-ease,94 myelodysplastic syndromes,95 multiplemyeloma , 96 interstitial pneumonitis , 97 Behcet’s dis-eases, polymyositis, dermatomyositis, systemic scle-rosis, and even SLE.98

FUTURE PERSPECTIVESIt is now clear that the usefulness of anti-TNF biologi-cal agents in combination with MTX or other biologi-cal agents lies not only in inducing clinical remissionbut also arresting structural damage in early RA.41These results have led to the introduction of a newstrategy whereby powerful combination therapy is ap-plied to early RA as an induction regimen. To take ad-vantage of this strategy, we need both to be able toidentify patients who have a poor prognosis and tohave access appropriate powerful treatment regi-mens. In this regard, remission can be expected to beinduced in 40% of patients with MTX+anti-TNF bio-logical agents , implying the presence of both re-sponders and non-responders to the regimen. It hasbeen demonstrated that −308 polymorphism at thepromoter region of TNF-α could be a predictivemarker for responders to TNF blockade therapy,99while others reported results to the contrary,100 Simi-lar approaches are used in Crohn’s disease.101-103Given that we can now have biological agents tar-

geting TNF, IL-1 and IL-6 as cytokines, CD20, andCTLA-4 as cell surface structures, it is necessary topredict the responders to each biological agents be-fore treatment or after early inhibition of biologicalagents, so that we can avoid toxicity of the drugs innon-responders , and provide efficientl treatment tothe right patients . Comprehensive profiling of themRNA expression strategy has recently been startedto identify and predict possible responder candidates.If we can identify the prediction markers, then tailor-made therapy using several biological agents maysoon be a clinical reality . Finally , issues of correcttreatment dose and duration for use of anti-TNF bio-logical agents in these inflammatory disorders re-mains to be considered.104,105

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