Expert Opinion on Investigational Drugs
`
`Monthly Focus: Pulmonary-Allergy, Dermatological, Gastrointestinal &
`Arthritis
`
`Anti-TNF agents in Crohn’s disease
`
`Gert Van Assche & Paul Rutgeerts
`Department of Internal Medicine, University Hospital Gasthuisberg, B-3000
`Leuven, Belgium
`
`The current treatment of Crohn’s disease is limited by a lack of long-term
`efficacy of corticosteroid therapy and the associated side effects. Biological
`treatment strategies aimed at neutralising immune responses, offer new
`opportunities for the management of chronic inflammatory disorders. In
`Crohn’s disease, anti-TNF agents have taken the lead in development of
`immune-modulating drugs since TNF is known to be a pivotal cytokine in
`this illness. Different strategies have been explored aimed at inhibiting TNF
`but at present, the majority of clinical data have been obtained with
`monoclonal antihuman TNF antibodies. The chimeric anti-TNF IgG1
`antibody infliximab (cA2, Remicade©, Centocor) has been proven,
`in
`multiple clinical trials, to be an effective and well tolerated therapy for the
`management of acute Crohn’s disease and recently this compound has
`obtained FDA and European Medicines Evaluation Agency
`approval.
`Although there are some concerns about immunogenicity of the anti-TNF
`antibody resulting in the formation of human antichimeric antibodies
`(HACA) as well as lymphoproliferative disorders, the clinical benefit in the
`treatment of refractory Crohn’s disease is a major therapeutic breakthrough.
`Further studies will be needed to establish the role and optimal dosing
`scheme of anti-TNF antibodies in maintenance of remission, monitor safety
`in the long run and to evaluate the effectiveness of alternative anti-TNF
`agents such as the TNF receptor/Fc fusion protein etanercept (Enbrel®,
`Immunex) and TNF synthesis inhibitor thalidomide.
`Keywords: Crohn’s disease, medical therapy, TNF
`
`Exp. Opin. Invest. Drugs (2000) 9(1):103-111
`
`1. Introduction
`
`Priority status within GI research and drug development has been assigned
`to Crohn’s disease and ulcerative colitis as they are the two main types of
`inflammatory bowel disease (IBD) and the incidence is rising both in the US
`and in Europe. IBD usually emerges in young adults and causes severe
`morbidity. Whereas in ulcerative colitis inflammatory lesions are restricted
`to the large bowel, Crohn’s disease can affect the entire GI tract. The
`majority of patients have terminal ileitis, colitis or a combination of both,
`even so isolated colitis, upper GI involvement and perianal disease are an
`integral part of the clinical picture. The current therapy for Crohn’s disease
`is limited by a lack of long-term efficacy and by the severity of side effects.
`Since Crohn’s disease is a chronically relapsing disease, the ideal treatment
`should be aimed at the induction and maintenance of remission without
`stricture formation. This should be reflected histologically in the restoration
`of mucosal inflammation and lack of excessive fibrosis of the deeper layers.
`
`Van Assche & Rutgeerts
`Anti-TNF agents in Crohn’s disease
`
`http://www.ashley-pub.com
`
`Review
`Introduction
`
`1.
`
`2. Role of TNF in IBD
`pathogenesis
`
`3. Biological inhibitors of
`TNF
`
`4. Mechanism of action and
`pharmacokinetics of
`anti-TNF agents
`
`5. Use of anti-TNF therapy in
`IBD
`
`5.1 Infliximab
`
`5.2 CDP571
`
`5.3 Etanercept
`
`5.4 Inhibitors of TNF
`synthesis
`
`6.
`
`Safety of anti-TNF agents
`in Crohn’s disease
`
`6.1 Immunogenicity and
`autoantibodies
`
`6.2 Infusion-related reactions
`
`6.3 Infections
`
`6.4 Malignancies
`
`7. Expert opinion
`
`Bibliography
`
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`103
`2000 © Ashley Publications Ltd. ISSN 1354-3784
`
`

`

`104 Anti-TNF agents in Crohn’s disease
`
`Corticosteroids have been the cornerstone for the
`treatment of severe Crohn’s disease over the last
`twenty years but
`this approach faces important
`drawbacks. Firstly, over time, the disease becomes
`refractory to the steroid treatment in most patients and
`secondly, there are adverse side effects when using
`steroids in the long-term. In the last decade, azathio-
`prine and its active metabolite 6-mercaptopurine have
`gained momentum in the maintenance of remission in
`Crohn’s disease. The reports on the use of other
`immune suppressive drugs such as methotrexate,
`cycloporine and FK-506 (tacrolimus) have been
`contradictory and at present, these regimens should
`be considered experimental.
`
`As in other chronic inflammatory conditions such as
`rheumatoid arthritis (RA),
`the emphasis of drug
`development
`for Crohn’s disease has been on
`biological therapies which target a single inflamma-
`tory mediator or pathway. This approach is surprising
`since intestinal
`inflammation in Crohn’s disease
`activates numerous inflammatory pathways which
`have a high degree of redundancy [1]. All experi-
`mental therapies are aimed at changing the balance
`between stimulatory and inhibitory inflammatory
`mediators in the inflamed bowel wall. For example,
`the anti-inflammatory cytokines IL-10 and IL-11 have
`been used both in animal models and in Crohn’s
`disease patients [2,3] with limited success. On the
`other hand, treatment strategies aimed at eliminating
`effects of the pivotal cytokine TNF have proven to be
`successful in a large number of patients with refrac-
`tory Crohn’s disease. This efficacy has led to the
`approval by the US FDA and the EMEA of the use of
`infliximab, of a chimeric monoclonal anti-TNF
`antibody, in the treatment of Crohn’s disease. This
`review discusses the molecular characteristics,
`efficacy and safety of various anti-TNF agents that are
`being developed for the treatment of Crohn’s disease.
`
`2. Role of TNF in IBD pathogenesis
`
`Although the aetiology of Crohn’s disease is multifac-
`torial and has not been fully elucidated, it is clear that
`chronic intestinal inflammation results from a disrup-
`tion in the balance between pro-
`and
`anti-inflammatory mediators that are present in the
`normal intestinal mucosa. A variety of these mediators
`are expressed in the inflamed bowel, but in experi-
`mental models of
`intestinal
`inflammation TNF is
`present at an early stage along with IL-1 and IL-6 [4]. In
`patients with Crohn’s disease TNF levels are elevated
`© Ashley Publications Ltd. All rights reserved.
`
`in the inflamed mucosa and also in the serum, when
`the patient has severe illness [5,6]. Both macrophages
`and activated T-lymphocytes are considered to be the
`cellular sources of TNF in gut mucosa. Although TNF
`production is probably not specific for intestinal
`inflammation causing Crohn’s disease, the predomi-
`nant Th1 phenotype of the CD4+-T cells makes it a
`key mediator of the inflammatory process responsible
`for this disease and a potential target for treatment.
`
`Transcription of the TNF gene positioned on the short
`arm of chromosome 6 leads to the secretion of
`inactive soluble 17 kD TNF-monomers that combine
`into 51 kD trimers, the active TNF ligand [7,8]. The
`transmembrane TNF precursor protein is processed
`by the TNF-α converting enzyme (TACE) that converts
`it into the 17 kD soluble monomere, while the unproc-
`essed 25 kD TNF remains attached to the cell
`membrane, where it is involved in cell-cell contact
`activation. The ligand binds two or three receptors
`simultaneously resulting in receptor polymerisation
`and signal-transduction. [9]. TNF-receptor activation
`triggers a variety of biological effects both locally
`including neutrophil attraction and granuloma
`formation and systemically such as the induction of
`the acute phase reaction. It is important to note that
`TNF-receptors in the cell membrane are cleaved by
`proteolytic enzymes and that this results in circulating
`soluble receptor
`fragments with TNF binding
`capacity, which can act as TNF scavengers.
`
`3. Biological inhibitors of TNF
`
`The anti-TNF agents currently in development for
`treating chronic inflammatory disorders can be mostly
`divided into three classes:
`
`(cid:129) anti-TNF antibodies
`
`(cid:129) TNF receptor/antibody fusion proteins
`
`(cid:129) inhibitors of TNF synthesis
`
`The anti-TNF antibodies bind soluble TNF ligand. This
`action neutralises the cytokine and in addition it may
`lead to lysis of cells with the membrane-bound TNF
`via complement fixation or cell mediated cytotoxicity.
`The major drawback of anti-human antibodies is the
`formation of antibodies against
`the molecule,
`potentially leading to their rapid clearance and to
`infusion reactions upon repeated exposure. At
`present, clinical experience in IBD has largely been
`with the Centocor chimeric human/mouse
`monoclonal antibody (mAb) infliximab. This first
`Exp. Opin. Invest. Drugs (2000) 9(1)
`
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`

`

`Figure 1: Schematic representation of the engineered anti-TNF antibodies infliximab and CDP571 and the TNF receptor/Fc fusion
`protein etanercept. The chimaeric antibody infliximab contains the variable regions of a murine anti-human TNF antibody. CDP571 is
`a humanised antibody in which only the hypervariable, complementarity determining regions are murine. Etanercept is entirely human
`and contains two p75 TNF receptor molecules. Note that an Fc region is present in both infliximab and etanercept which are derived of
`an IgG1, whereas CDP571 is an IgG4.
`
`Van Assche & Rutgeerts 105
`
`IgG1 antibody
`
`variable
`
`constant
`
`Fc portion
`
`Chimeric human/mouse
`antibody
`
`Humanised human/mouse
`antibody
`
`Human receptor/Fc
`fusion protein
`
`murine
`human
`
`75 % human
`
`Fc
`
`95 % human
`
`100 % human
`
`Fc
`
`Infliximab
`
`CDP571
`
`Etanercept
`
`generation engineered protein is produced by a
`murine myeloma cell
`line transfected with cDNA
`encoding the constant domains of the human IgG1
`antibody [10]. Since the protein is still 25% murine
`(Figure 1) it induces the formation of HACA. From
`the second generation of
`‘humanised’ antibodies,
`CDP571 (Celltech) is currently being evaluated for the
`treatment of Crohn’s disease. This protein is 95%
`human, but still gives rise to human antihuman
`antibodies (HAHA) [11]. For the TNF receptor fusion
`protein, etanercept and for inhibitors of TNF synthesis
`such as thalidomide, phase-I clinical
`trials are at
`present being conducted for the treatment of Crohn’s
`disease. Inhibitors of TACE that inhibit the release of
`soluble TNF may enter clinical
`trials for Crohn’s
`disease in the near future.
`
`4. Mechanism of action and
`pharmacokinetics of anti-TNF agents
`
`The chimaeric antibody cA2 (infliximab) binds with
`high affinity to the membrane bound TNF monomers
`© Ashley Publications Ltd. All rights reserved.
`
`and to the soluble TNF trimers [12,13]. Upon binding
`to TNF on cell membranes, the human IgG1, part of
`the molecule triggers both complement activation and
`cell mediated cytotoxicity. In vivo studies have shown
`that
`infliximab induces a decrease in mucosal
`pro-inflammatory cytokines associated with the
`activation of Th1-cells [14]. Interestingly infliximab
`acts as a cytokine scavenger prolonging the serum
`half-life of TNF probably by protecting it
`from
`proteolytic degradation. [15]. The serum t½ values for
`infliximab vary between 9.5 and 14 days for the 5 - 20
`mg/kg infusion dose [15,16].
`
`The humanised antibody CDP571 (Celltech) consists
`of a human IgG4 (Figure 1) and therefore it does not
`activate complement and does not
`trigger
`cell-mediated cytotoxicity. CDP571 probably
`functions as a scavenger of soluble TNF trimers and
`blocks membrane bound TNF. The serum half-life for
`the 5 mg/kg dose is 14 days, but unlike infliximab,
`CDP571 was detectable for up to 12 weeks after a
`single dose of 2 - 10 mg/kg.
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`

`106 Anti-TNF agents in Crohn’s disease
`
`Figure 2: Schematic representation of mechanisms of action of anti-TNF agents infliximab, CDP571 and etanercept.
`
`lysis of TNF-expressing cells
`infliximab
`
`apoptosis of TNF-expressing cells
`infliximab ?
`
`complement activation
`cell mediated cytotoxicity
`
`T- cells
`macrophages
`
`neutralization of membrane-bound
`TNF trimers
`infliximab, CDP571
`
`neutralization of soluble TNF trimers
`infliximab, CDP571, etanercept
`
`The fusion protein, etanercept consists of the TNF
`binding region of the human 75 kD receptor linked to
`the Fc domain of IgG1. Each molecule carries two TNF
`receptors (Figure 1). The fusion protein has a higher
`affinity for TNF trimers than the native soluble
`receptor fragments and it has an increased serum
`half-life (± 5 days) [17,18].
`
`5. Use of anti-TNF therapy in IBD
`
`5.1 Infliximab
`Infliximab was first used in a 14-year old girl with
`Crohn’s disease refractory to medical treatment, at a
`dose of 10 mg/kg, given twice with a two week
`interval. The patient went into remission lasting for
`three months [19]. Subsequently in the same centre,
`ten patients with Crohn’s disease refractory to steroid
`treatment, were included in a pilot study. Eight
`consecutive patients were treated with 10 mg/kg and
`two additional patients with 20 mg/kg to assess
`product safety (Table 1). Dramatic results with rapid
`onset were seen in nine out of ten patients, who
`reported clinical improvement within one week and
`went into remission (CDAI index < 150) at two weeks.
`The clinical remission lasted for eight weeks and at
`© Ashley Publications Ltd. All rights reserved.
`
`after four weeks endoscopic and histological evalua-
`tion showed a dramatic improvement in these nine
`patients [20].
`
`A dose finding study was then initiated, enrolling 20
`patients with moderate to severe Crohn’s disease
`(CDAI 220-400) refractory to steroid treatment. At four
`weeks clinical improvement as defined by a 70 point
`drop in the CDAI score was observed in 40% patients
`in the 1 mg/kg group and in 80% in all higher dosage
`groups (5 - 10 - 20 mg/kg). At week 12, the 5, 10 and
`20 mg/kg group had comparable response rates (67%,
`80% and 50% respectively). However, optimal
`remission rates (CDAI < 150) at week two were
`observed in the 10 mg/kg group. The clinical
`response of the patients in the high dose groups was
`reflected in the endoscopic activity score [21]. For
`Phase IIb/Phase III placebo-controlled trials the
`dosing scheme was based on this study (5 – 10 - 20
`mg/kg).
`
`A placebo-controlled multicentre Phase IIb/III trial
`was subsequently initiated in which 108 patients with
`refractory Crohn’s disease were included [22]. The
`continuation of concomitant conventional
`therapy
`was allowed. Patients received placebo or 5, 10 or 20
`mg/kg infliximab at the start. At four weeks clinical
`Exp. Opin. Invest. Drugs (2000) 9(1)
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`

`

`Table 1: Clinical trials investigating the use of anti-TNF antibodies in Crohn’s disease.
`
`Van Assche & Rutgeerts 107
`
`Indication
`
`Patients
`
`Duration
`(weeks)
`
`Clinical remission
`
`Ref.
`
`Clinical improvement (% of
`patients)
`Infliximab, cA2, Centocor
`infliximab
`placebo
`(10 mg/kg)
`100%
`80%
`17%
`50%
`26%
`56%
`35%
`66%
`CDP571, Celltech
`CDP571
`CDP571
`placebo
`(5 mg/kg)
`(5 mg/kg)
`[27]
`0%
`30%
`50%
`55%
`8
`30
`active CD
`Note: For all infliximab clinical trials the results of the 10 mg/kg dosage are represented since this dose was used in all studies.
`Clinical improvement was defined as a decrease of at least 70 points in the CDAI (Crohn’s Disease Activity Index). Remission was
`considered to occur if the CDAI dropped below a score of 150. For the trial in patients with fistulae clinical improvement was defined
`as closure of at least 50% of draining fistulae and remission as closure of all fistulae.
`
`active CD
`active CD
`active CD
`fistulae
`maintenance
`
`10
`20
`108
`94
`73
`
`8
`4
`4
`18
`44
`
`infliximab
`(10 mg/kg)
`100%
`20%
`25%
`38%
`51%
`
`placebo
`
`4%
`13%
`21%
`
`placebo
`
`[20]
`[21]
`[22]
`[26]
`[25]
`
`improvement was observed in 17% (4/24) of patients
`receiving placebo and in 82% (13/27) of the 5 mg/kg
`infliximab group (p = 0.005). The response rates in the
`higher dose groups were lower than those in the 5
`mg/kg group. Clinical remission (CDAI score < 150)
`occurred in 48% of the patients receiving 5 mg/kg
`versus 25% in both the 10 and 20 mg/kg group. In the
`placebo group only 4% of the patients went into
`clinical remission.
`
`Additional information on the effect of infliximab on
`inflammatory lesions in active Crohn’s disease was
`gathered in the European centres involved in this first
`Phase IIb/III study. At week four, a close correlation
`between the clinical response to infliximab on the one
`hand and improvement
`in both endoscopic and
`histological scores was observed [23,24]. The
`reduction in the severity of inflammation coincided
`with the disappearance of TNF and downregulation of
`adhesion molecules in the lamina propria [24].
`
`This study provided firm evidence of the effectiveness
`of anti-TNF antibodies in the acute management of
`refractory Crohn’s disease both for clinical improve-
`ment and for remission. Long-term maintenance of
`remission was evaluated in a follow-up study where
`patients who had shown a response to the initial
`infusion of infliximab or placebo were again random-
`ised to receive 10 mg/kg infliximab or placebo at
`weeks 12, 20, 28 and 36. In addition patients who had
`© Ashley Publications Ltd. All rights reserved.
`
`entered the open label study with 10 mg/kg after a
`failure of response to the first infusion were offered
`the possibility to be enrolled in the repeated infusion
`study. Seventy-three patients were included and
`patients were followed until week 48 (8 weeks after
`their last infusion). At week 48 a persistent clinical
`response was noted in 66% (24/36 of infliximab versus
`35% (13/37) of placebo treated patients (P < 0.01). The
`difference between remission rates in the placebo and
`infliximab group was also significant [25]. Since the
`optimal dose and dosing interval for maintenance
`therapy can not be distilled from this study and
`because there was a high variance in concomitant
`therapy (amino-salicylates, steroids and azathioprine)
`among the 73 patients, the FDA did not approve of the
`use of infliximab in maintenance therapy for Crohn’s
`disease.
`
`As enterocutaneous fistulae are a debilitating compli-
`cation of Crohn’s disease, a second Phase III study
`was directed towards patients with this complication.
`The study was designed as a multicentre, double-
`blind placebo-controlled trial. Ninety-four patients
`with abdominal wall or perianal fistulae were treated
`with three infusions of either placebo or cA2
`(infliximab) at 5 or 10 mg/kg [26]. Three infusions
`were given at week 0, 2 and 6 and patients were
`followed through week 18. Clinical improvement was
`defined as the closure of at least 50% of draining
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`

`108 Anti-TNF agents in Crohn’s disease
`
`fistulae for four weeks or more and occurred in 26%
`(8/31) of placebo patients versus 67 (21/31) in the 5
`mg/kg and 56% (18/32) in the 10 mg/kg infliximab
`group (p = 0.002). In addition, remission, defined as
`the closure of all draining fistulae for ≥ 4 weeks, was
`observed in a significantly higher proportion of
`infliximab treated patients (Table 1). The onset of
`response was also more rapid in the cA2 group as
`compared to the placebo group (median time to
`response 14 days [cA2] versus 42 days [placebo]).
`
`Taken as a whole these studies, which have enrolled a
`total of 233 patients, have shown that infliximab is
`highly effective in the induction of remission in
`moderate to severe Crohn’s disease, more particularly
`since most patients were refractory to conventional
`therapy including steroids and immunosuppressives.
`Moreover, the data suggest that there may be a role for
`the antibody given as repeated infusions in the
`maintenance of clinical remission.
`
`5.2 CDP571
`One single dose, multicentre, placebo-controlled,
`double-blind trial
`investigating the efficacy of the
`humanised antibody CDP571 in Crohn’s disease has
`been reported. [27]. The trial enrolled 30 patients with
`moderate to severe refractory Crohn’s disease who
`were treated with a single infusion of either placebo
`or CDP571 at 5 mg/kg. The primary end point in this
`study was defined as a decrease in the median CDAI at
`week two. In the CDP571 treated patients, the median
`CDAI dropped 96 points in two weeks (263 to 267, p <
`0.001) whereas there was no significant change in the
`placebo group. The study suggests that there may be a
`role for CDP571 in the short-term management of
`refractory Crohn’s disease, although the results of
`now completed studies will be needed to evaluate the
`optimal dosing scheme and the long-term effects.
`
`5.3 Etanercept
`At present no clinical studies focusing on the use of
`the TNF fusion protein, etanercept in Crohn’s’ disease
`have been completed.
`
`5.4 Inhibitors of TNF synthesis
`The use of small molecule TNF-inhibitors such as
`PDE4 inhibitors and thalidomide for treating Crohn’s
`disease is still in an early phase of development. The
`PDE4 inhibitor oxpentifylline has been used in 16
`patients with steroid dependent Crohn’s disease in a
`non-blinded study with a single dose of 400 mg q.i.d.
`© Ashley Publications Ltd. All rights reserved.
`
`[28]. After 4 weeks, there was no evidence of clinical
`or endoscopic improvement in these 16 patients. For
`thalidomide, preliminary results suggest
`that
`this
`molecule may have a role in the acute treatment of
`Crohn’s disease although the drug carries the threat of
`adverse side effects such as birth defects and
`neuropathy [29]. Thalidomide is used in other chronic
`inflammatory diseases associated with oral aftous
`lesions and may prove useful in the management of
`patients with oro-pharyngeal Crohn’s disease.
`
`6. Safety of anti-TNF agents in Crohn’s
`disease
`
`Anti-TNF agents and more specifically infliximab has
`been used in over 20,000 patients, many in controlled
`trials and is generally well tolerated. However, as
`TNF-α is a pleiotropic cytokine with a variety of
`biological effects, inhibition of the molecule raises
`important safety considerations including immuno-
`genicity, infusion-related reactions, infections and risk
`of malignancy. It is important to note that the side
`effects of infliximab are noted from data obtained in
`Crohn’s disease as well as in RA.
`
`6.1 Immunogenicity and auto-antibodies
`Of all Crohn’s disease patients enrolled in clinical
`trials with infliximab 13% developed HACA. The
`presence of HACA may predispose patients to
`infusion-related reactions and to rapid clearance of
`infliximab.
`Immune modifying therapy such as
`steroids, azathioprine/6-mercaptopurine appears to
`protect against the formation of HACA (10% in this
`group versus 23% in patients without concomitant
`immune modulating therapy) [16]. Repeated exposure
`to infliximab after a prolonged interval may lead to a
`serum-sickness type delayed hypersensitivity
`reactions as was recently reported in a retreatment
`trial [30]. Classical serum sickness symptoms including
`myalgia, fever, rash, urticaria, polyarthralgia and facial
`oedema were found in 10 out of 40 patients of whom
`6 were admitted to hospital. All the patients tested had
`high titres of HACA and rapidly cleared circulating
`infliximab. These reactions urged the manufacturer to
`request shorter intervals for repeated infliximab
`infusions. HAHA were found in 35% and 16% of
`patients treated with CDP571 and etanercept respec-
`tively although the clinical
`implication of HAHA
`formation has not been established.
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`

`

`Three patients (one with Crohn’s disease and two
`with RA) developed a lupus-like syndrome after
`treatment with infliximab, although anti-double
`stranded (ds)-DNA-antibodies were found in 8.6% of
`all patients. The auto-antibodies disappeared from the
`serum after discontinuation of infliximab treatment.
`No data on auto-antibody formation after treatment
`with CDP571 are available, but etanercept treatment
`may result in the formation of antinuclear antibodies
`and anti-ds-DNA antibodies. Anti-ds-DNA 15%
`(etanercept) versus 4% (placebo).
`
`6.2 Infusion-related reactions
`Reactions related to infliximab infusion were defined
`as any adverse event occurring during or within 2 h
`post-infusion. Among infliximab-treated patients, 16%
`experienced an adverse event as compared to 6% of
`controls. Of 1207 infliximab infusions, 5% were
`associated with aspecific symptoms such as fever or
`chills, 1% with cardiopulmonary reactions (chest pain,
`dyspnea and hypotension) and 1% with urticaria
`and/or pruritus. Patients who developed HACA were
`more at risk for infusion reactions whereas concomi-
`tant immune-modulator treatment protected against
`reactions to infliximab infusion [16].
`
`Local reactions at the injection site were observed in
`up to 37% of patients treated subcutaneously with
`etanercept although discontinuation of the therapy
`was never necessary.
`
`6.3 Infections
`Although the total number of infections reported after
`treatment with infliximab was higher than in controls
`(21% vs. 11%) this did not result in an increase of the
`incidence of serious infections requiring antibiotic
`treatment. In the calculation, an adjustment was made
`for the length of follow-up (average of 22 weeks for
`infliximab and 12 weeks for placebo).
`
`Serious infections in the infliximab treated patients
`included pneumonia, cholecystitis, cellulitis and
`catheter-related sepsis. In addition, after treatment
`with CDP571 and etanercept there is no increased risk
`of serious infections. In patients with enterocutaneous
`fistulae treated with infliximab, newly formed
`abscesses were observed in 12% [26]. This is probably
`not so much due to impaired host defence, but rather
`reflects the natural evolution of relapse in anal
`Crohn’s disease and by rapid closing of the cutaneous
`orifice with entrapment of faecal material.
`© Ashley Publications Ltd. All rights reserved.
`
`Van Assche & Rutgeerts 109
`
`It is of interest to note that no opportunistic infections
`were reported in patients treated with infliximab,
`which is in accordance with the absence of
`leucopenia and of impairment of T-cell proliferation
`after infliximab treatment.
`
`6.4 Malignancies
`Due to the pleiotropic nature of the TNF bioactivity,
`which includes tumour suppression,
`there is a
`theoretical risk of increased malignancy with anti-TNF
`agents. An elevated incidence of
`leukaemia and
`lymphoma has been observed in patients receiving
`drugs for long-term immunosuppressive agents,
`including Crohn’s disease patients. Of 394 patients
`treated with infliximab one patient with Crohn’s
`disease developed a non-Hodgkin lymphoma. This
`patient had been diagnosed with Crohn’s disease 30
`years before anti-TNF treatment and had been on
`long-term immune modulator therapy. Four more
`lymphomas were found in infliximab treated RA
`patients. In the largest patient cohort reported in the
`literature by Greenstein, 4 in 1,480 Crohn’s disease,
`patients developed a lymphoma in a 20 year time
`interval (1960 - 1982) [30]. Therefore, for Crohn’s
`disease one case of lymphoma does not allow to
`conclude that there is an increased incidence after
`treatment with infliximab although it warrants a
`heightened alertness towards lymphoproliferative
`disorders in these patients.
`
`7. Expert opinion
`
`Anti-TNF agents are the first representatives of new
`biological
`therapies for the treatment of Crohn’s
`disease, opening both new opportunities for patients
`with a debilitating disease and a challenge for drug
`development. The bulk of experience in clinical trials
`and recently also as a registered treatment in the US
`has been obtained with Centocor’s anti-TNF antibody
`infliximab. This compound has been demonstrated to
`be effective in the induction of clinical improvement
`and remission of moderate to severe active Crohn’s
`disease, refractory to standard treatment
`in most
`patients. In addition, anti-TNF therapy appears to be
`effective for both Crohn’s ileitis and colitis as for
`complicated disease with enterocutaneous fistulae.
`However, since infliximab induces rapid healing of
`inflamed tissue as was first observed in perianal
`fistulae, there is some concern about the potential
`induction or worsening of strictures by anti-TNF
`treatment. The role of anti-TNF agents in the
`Exp. Opin. Invest. Drugs (2000) 9(1)
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`110 Anti-TNF agents in Crohn’s disease
`
`maintenance of remission has not been clearly
`established at present and therefore immune-
`modulator treatment such as azathioprine is not
`discontinued after
`infliximab infusion even if
`repeated infusions of infliximab can now be offered.
`More studies will be needed to evaluate the benefit of
`combining anti-TNF therapy with methotrexate in
`Crohn’s disease. This combination has been shown to
`be superior to infliximab monotherapy in RA [32].
`
`Although tolerance to anti-TNF agents is generally
`very good, infusion reactions and delayed hypersensi-
`tivity have been observed. Infusion reactions are
`generally mild and easily controlled with standard
`measures. The optimal dosing interval and concomi-
`tant therapy to avoid the formation of HACA (for
`infliximab) and HAHA (for CDP571), which are
`clearly associated with reactions to repeated infusion,
`needs to be determined in the future. As far as the risk
`for lymphoproliferative disorders is concerned, a
`careful and long-term follow-up of
`the growing
`cohort of Crohn’s disease patients treated with
`infliximab will be needed. As data on the use of other
`TNF-binding molecules such as CDP571, etanercept
`and thalidomide are accumulating, a further
`expansion of
`the use of anti-TNF agents in the
`treatment of IBD is to be expected.
`
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