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`Ann Rheum Dis 1999;58:(Suppl I) I114–I120
`
`Anti-TNF antibody treatment of Crohn’s disease
`
`S J H van Deventer
`
`Crohn’s disease and ulcerative colitis are the two
`idiopathic chronic inflammatory bowel diseases.
`Although these diseases may show substantial
`phenotypic overlap, it is widely accepted that
`these represent distinct pathogenic entities. The
`cause of neither ulcerative colitis nor Crohn’s
`disease is known, and genetic as well as environ-
`mental factors have been implicated. Previous
`reports implicating single microbial pathogens
`(Mycobacterium paratuberculosis, measles)
`in
`Crohn’s disease are controversial and have not
`been confirmed.1–11 On the other hand, evidence
`that antigen driven ill controlled activation of
`mucosal T lymphocytes is a major disease
`mechanism has accumulated in recent years,
`and this has led to novel therapeutic strategies. I
`here review the clinical results of anti-TNF anti-
`body treatment against
`the background of
`current knowledge of the regulation of mucosal
`immune activation.
`
`Current treatment of Crohn’s disease is
`insuYcient
`The incidence of Crohn’s disease is increasing
`in Western Europe and the USA, and is now
`6–10/100 000 inhabitants.12 13 Because Crohn’s
`disease is a lifetime disorder, the prevalence is
`at least 20-fold higher. The clinical symptoms
`and signs of Crohn’s disease can be rather non-
`specific, including abdominal pain, weight loss,
`fatigue and (bloody) diarrhoea, but most
`patients with active disease have an increased
`erythrocyte sedimentation rate (ESR) or raised
`circulating C reactive protein concentrations.
`Although commonly known as “terminal
`ileitis”, only about 30% of patients have disease
`restricted to the terminal
`ileum, and most
`patients have isolated large bowel, or combined
`small and large bowel involvement. The disease
`may also involve the oral cavity, oesophagus
`and stomach, and can occur outside the intes-
`tinal tract, in particular in the perineal area
`(histologically characterised by granulomatous
`lymphangitis) or located in surgical wounds.
`About 20% of patients have perianal fistulas,
`and the presence of such lesions is a substantial
`risk factor for eventual complete loss of the
`large bowel and construction of a permanent
`ileostoma.14 Lifestyle factors may have an
`important
`impact on disease activity, and
`smoking of cigarettes worsens disease activity
`and leads to frequent relapses (interestingly, in
`ulcerative colitis smoking is protective).15–17
`Overall survival of Crohn’s disease patients is
`not diVerent from controls, but about 70% of
`all patients undergo one or more surgical pro-
`cedures in the course of disease, 25% of
`patients with large bowel involvement eventu-
`ally end with a permanent ileostoma, and
`despite current medical treatment, a cross sec-
`tional population based study indicated that
`
`30% of patients have active disease.18 19 Medi-
`cal treatment of Crohn’s disease consists of
`administration of high dose mesalazine in mild
`cases, corticosteroids in moderate to severe
`disease, and immunosuppressives, in particular
`azathioprine and methotrexate for patients
`with corticosteroid dependent or corticoster-
`oid refractory disease.20 21 After initial enthusi-
`asm, several studies have failed to confirm a
`treatment benefit of oral cyclosporine, and the
`use of this drug is now restricted to compli-
`cated fistulas or extra-intestinal disease.22–25
`None of the aforementioned drugs is the ideal
`therapeutic reagent. Mesalazine is relatively
`non-toxic and well tolerated, but the ability to
`induce remissions is limited and a recent meta
`analysis failed to demonstrate a maintenance
`eVect.26 Corticosteroids are eVective and con-
`tinue to be the mainstay of treatment for
`patients with active Crohn’s disease, but are
`associated with many side eVects. Moreover,
`corticosteroid treatment fails to induce remis-
`sions in 20–30% of patients, and a substantial
`percentage of patients become corticosteroid
`dependent.27 Budesonide is a glucocorticoid
`with a very high aYnity for the glucocorticoid
`receptor, and is eVective in inducing remissions
`while have significantly reduced systemic side
`eVects as a result of eVective first-pass liver
`metabolism.28–30 However, no formulation has
`been demonstrated to eVectively deliver
`budesonide to the large bowel, and no
`corticosteroid,
`including budesonide, eVec-
`tively maintains remissions.31 32 Azathioprine
`has been long used in Crohn’s disease and is
`relatively safe: about 7% of patients develop
`side eVects and another 7% infectious compli-
`cations (in particular viral infections).33–36 The
`main place in the therapeutic arsenal
`is
`treatment of corticosteroid refractory or corti-
`costeroid dependent patients, and treatment of
`fistulas. Although azathioprine has an impor-
`tant place in the therapeutic repertoire in
`Crohn’s disease, the response to treatment is
`slow, a significant percentage of patients do not
`respond to treatment, and five to six patients
`need to be treated to prevent a single relapse.36
`Methotrexate is widely used in Crohn’s disease
`(at rather high doses: 15–25 mg/week), and has
`been shown to be eVective in allowing discon-
`tinuation of corticosteroid treatment in refrac-
`the long term
`tory patients.37 38 However,
`eYcacy of methotrexate in Crohn’s disease is
`not known, and therapeutic eYcacy tends to
`decrease during prolonged administration.
`One of the major problems with current
`medical treatment is the inability to change the
`natural course of disease. After successful
`medical
`induction of remission, 60–70% of
`patients
`experience
`a
`relapse within 12
`months.31 39 Large bowel resections are also
`
`Laboratory for
`Experimental Internal
`Medicine, Academic
`Medical Centre,
`Meibergdreef 9, 1105
`AZ Amsterdam, the
`Netherlands
`
`Correspondence to:
`Dr S J H van Deventer.
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`associated with a high relapse rate, and
`(asymptomatic) ulcerations of
`the surgical
`anastomosis are frequently observed 3–12
`months after ileocaecal resection.40 41 Fortu-
`nately, the rate of clinical relapses after this lat-
`ter procedure is much lower and amounts to
`about 50% after five years.42 Finally, it remains
`unknown what the preferred treatment strategy
`is in Crohn’s disease. There are no data to
`indicate that the historical step up approach,
`starting with mesalazine and adding cortico-
`steroids and immunosuppressives, is superior
`to immediate treatment with immunosuppres-
`sives or vice versa, nor is it known whether the
`choice of initial treatment changes the long
`term outcome of the disease.
`
`The immune defect of Crohn’s disease
`A common lesion observed early in Crohn’s
`disease is the aphtoid lesion, a small ulcer that
`originates from mucosal lymphoid aggregates
`that are scattered throughout the bowel. These
`lymphoid aggregates are covered by a special-
`ised type of epithelial cells, named M cells that
`are involved in the processing of gut lumen
`antigens.43 44 Later in the course of disease a
`more general and transmural activation of
`lamina propria and submucosal T lymphocytes
`is observed, but even in patients with severe
`disease this is poorly reflected in the peripheral
`blood. The inflamed mucosa also shows an
`influx of granulocytes and activated mono-
`cytes, which produce significant amounts of
`eicosanoids, cytokines and chemokines. The
`mononuclear cells may be organised in granu-
`lomas, which are considered a hallmark of
`Crohn’s disease. In progressive disease the
`aphtoid lesions progress to ulcers, which may
`coalesce to form longitudinal “railroad” tracks
`that may run along the entire length of the large
`bowel. Strictures may form at sites of extensive
`inflammation, and are frequently observed at
`surgical anastomoses. With the exception of
`transmural inflammation and the occurrence
`of granulomas, the histological
`features of
`Crohn’s disease tend to be non-specific and of
`little help in establishing a diagnosis. Recently
`however, specific changes of T lymphocyte
`function and cytokine patterns have been
`recognised that distinguish Crohn’s disease
`from other inflammatory bowel disorders (see
`below).
`A major breakthrough in the insight into the
`pathogenesis of Crohn’s disease was a result of a
`series of—rather
`serendipitous—findings
`in
`mice with various (induced) defects of T
`lymphocyte
`function
`(reviewed
`in
`references45–48). In addition, T lymphocyte trans-
`fer models form Balb/C into SCID mice have
`yielded pivotal
`results that will be briefly
`summarised here. When CD4+ T lymphocytes
`are transferred from normal Balb/C mice into
`SCID mice, various organs including the small
`and large bowel mucosa become repopulated
`with donor cells, without
`initially causing
`disease, but when only a subpopulation of naïve
`cells
`(CD4+CD45RBhigh)
`is
`transferred,
`the
`recipient mice develop inflammatory disease of
`the large bowel (and of the stomach). This
`disease
`is
`characterised by Th1 biased
`
`production of lamina propria (T lymphocyte)
`cytokines.
`Interestingly, co-transfer of
`the
`CD4+CD45RBlow population prevents develop-
`ment of disease, and disease does not occur in
`germ free animals.49–51 Moreover, it has been
`demonstrated that a high IL10 producing T cell
`population (called Tr1) was able to prevent
`CD4+CD45RBhigh transfer colitis.52 53 Hence, in
`this model, disease can be caused by a subpopu-
`lation of CD4+ T lymphocytes, which are con-
`trolled by another CD4+ subpopulation.54 55
`IL10 seems
`to be one of
`the important
`regulatory cytokines in this model, and the
`initiation of disease is antigen dependent.
`Therefore, the key players in immune mediated
`inflammation in the gut mucosa are intestinal
`(bacterial) antigens, reactive T lymphocytes,
`and regulatory T lymphocytes.
`Initial studies on mucosal cytokine (IL1♢,
`IL6, IL8) expression did not clearly distinguish
`Crohn’s disease from ulcerative colitis or infec-
`tious colitis, but more recent data allow the
`conclusion that Crohn’s disease is a Th1 biased
`condition. As compared with various controls
`(normal subjects, ulcerative colitis patients)
`increased expression of IL12 and IL18 by
`lamina propria mononuclear cells has been
`reported in Crohn’s disease, and lamina
`propria T lymphocytes
`produce more
`IFN♤.56–58 Increased TNF♡ expression occurs
`both in Crohn’s disease and in ulcerative
`colitis, but the distribution of the source cells
`diVers: only in Crohn’s disease cells located in
`the deep lamina propria and submucosa
`produced TNF♡.59 60 In addition, lamina pro-
`pria T lymphocytes from Crohn’s disease
`patients show increased IL2 dependent prolif-
`eration, and are relatively resistant to apoptosis
`induced by CD2 activation, IL2 depletion or
`engagement of Fas.61 62 This phenomenon is in
`part explained by an increased ratio of
`intracellular expression of the proteins Bax
`(pro-apoptotic) and Bcl-2 (anti-apoptotic; see
`below). It should be noted that apoptosis
`resistance is not caused by mucosal inflamma-
`tion in itself because it is not observed in
`ulcerative colitis.62
`How can these results be translated in
`clinically eVective treatment strategies? Theo-
`retically, multiple strategies would be expected
`to be eVective, including (1) a reduction of the
`antigenic pressure within the gut lumen, (2)
`interference with proliferation of activated T
`lymphocytes, (3) interference with transcription
`of the genes encoding pro-inflammatory cy-
`tokines, prevention of release of cytokines by
`inflammatory cells, or neutralisation of released
`cytokines,
`(4)
`administration of
`counter-
`regulatory cytokines. Indeed there is evidence
`that conventional treatment modalities owe their
`eYcacy to interference with these mechanisms.
`For example, reduction of the gut luminal anti-
`genic pressure by surgical faecal diversion, or
`administration of antibiotics is known to de-
`crease the activity of Crohn’s disease and
`re-introduction of faeces in the diverted bowel
`loop frequently leads to an exacerbation of
`disease.63 64 Azathioprine, methotrexate and
`mycophenolate mofetil are though to owe their
`beneficial eVects to inhibition of lymphocyte
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`van Deventer
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`proliferation, and prednisone interferes with
`cytokine transcription. More importantly, a
`wide range of novel intervention strategies has
`been based on these principles, including inhibi-
`tors of cytokine gene transcription, inhibitors of
`cytokine releasing enzymes, administration of
`recombinant human IL10, and neutralisation of
`pro-inflammatory cytokines.65–73 I will here focus
`on TNF♡ neutralising strategies, with particular
`emphasis on their mode of action.
`
`bind lymphotoxin, which is importantly in-
`volved in humoral immune responses.
`In conclusion,
`the biological eVects of
`various TNF♡ inhibiting strategies importantly
`diVer, and results obtained with a certain (class
`of) inhibitors cannot be simply extrapolated to
`other reagents. The determinants of the clinical
`eYcacy of TNF inhibiting strategies are only
`partly known, and need to be studied in more
`detail.
`
`TNF♡ blocking strategies
`The production of TNF♡ is tightly regulated at
`the transcriptional,
`translational and post-
`translational levels, providing many opportuni-
`ties for therapeutic intervention. Increase of the
`intracellular cAMP concentration reduces the
`TNF transcription rate, and this is the mecha-
`nism by which noradrenaline
`(norepine-
`phrine), pentoxifylline and, in part, thalido-
`mide reduce TNF♡ transcription.74–80 Another
`approach is to inhibit the nuclear translocation
`of the transcription factor NF♭B that is impor-
`tant for the transcription of multiple cytokine
`genes including TNF♡. After translation, the
`TNF♡ protein needs to be proteolytically
`cleaved at the cell membrane, to be released as
`the homotrimeric soluble mature TNF♡. Un-
`cleaved TNF remains membrane bound, and is
`biologically active by engaging the p75 TNF
`receptor in cell to cell interactions. Cleavage of
`TNF♡ is caused by a specific metalloproteinase
`inhibitor (TNF♡ converting enzyme—TACE)
`and can be inhibited by specific metalloprotei-
`nase inhibitors.81 82 Finally, antibodies and
`soluble TNF receptor proteins can bind and
`neutralise soluble TNF♡, and some also recog-
`nise membrane bound TNF♡. It should be
`noted that important diVerences exist in the
`biological eVects as well as the clinical eYcacy
`(as far as has been tested) of these diVerent
`approaches. Oxpentifylline (a pentoxifylline
`analogue) did not change the activity of
`Crohn’s disease although it
`reduced the
`production of TNF♡ by ex vivo stimulated
`monocytes, indicating that either targeting of
`membrane bound TNF♡ is of pivotal impor-
`tance or that TNF♡ production by cells other
`than monocytes
`(that
`is, T lymphocytes)
`should be targeted.83 84 Various inhibitors of
`NF♭B are currently being evaluated in animal
`models of inflammatory bowel disease, and
`some have shown eYcacy.65 85 However, inhibi-
`tion of NF♭B is not synonymous with TNF♡
`inhibition, and may have complex eVects on
`TNF♡ induced biological eVects, such as
`apoptosis. Known NF♭B inhibitors, such as
`aspirin, do not
`reduce disease activity of
`Crohn’s disease, but indeed may induce severe
`flares. TACE inhibitors may eVectively release
`of TNF♡ by monocytes and lymphocytes, in
`vitro as well as in vivo, but do not change the
`expression of membrane bound TNF♡ that is
`important
`in interactions of
`immune cells.
`Finally, even monoclonal antibodies and TNF
`receptor constructs may have diVerent biologi-
`cal activities: monoclonal anti-TNF♡ antibod-
`ies are specific for TNF♡, but designer
`molecules using the p75 TNF receptor also
`
`TNF♡ antibodies in Crohn’s disease
`The first Crohn’s disease patient to be treated
`with anti-TNF♡ antibody (infliximab) was a
`young girl with severe Crohn’s colitis, refrac-
`tory to treatment including prednisone and
`azathioprine.86 She received two infusions of
`the antibody at a dose of 10 mg/kg, within two
`weeks, and the results were remarkable: within
`a few days stool consistency and frequency
`normalised, the ESR decreased, and the exten-
`sive intestinal ulceration healed. Eventually she
`relapsed, and after undergoing several surgical
`procedures now has a permanent ileostoma.
`Encouraged by this initial result, a small
`uncontrolled pilot study in 10 patients with
`treatment refractory Crohn’s disease was per-
`formed, and eight of nine evaluable patients
`(one patient underwent surgery rapidly after
`the infusion) showed a dramatic response after
`infusion of a single infliximab dose of 10 (eight
`patients) or 20 (two patients) mg/kg.87 The
`eVects of treatment were rapid (within days),
`increased serum C reactive protein and se-
`creted phospholipase A2 (sPLA2) concentra-
`tions rapidly reduced in all patients and intesti-
`nal
`ulcerations
`healed.87 88 This
`latter
`observation was remarkable, because no other
`drug treatment had been demonstrated to
`eVectively heal the primary lesion (the mucosal
`ulcer) of Crohn’s disease. The first controlled
`clinical trial using infliximab included 108
`patients who were randomised to receive
`infliximab (5 or 10 mg/kg) or placebo.89
`Non-responders were oVered an open label
`infusion of infliximab (10 mg/kg) and all even-
`tual responders were re-randomised to receive
`infliximab (10 mg/kg) or placebo every eight
`weeks. The results of this study showed that
`infliximab treatment
`induced significantly
`more therapeutic responses and complete
`clinical remissions as compared with placebo
`(infliximab 5 mg/kg: 81%; placebo 17%) and
`that
`these therapeutic responses could be
`maintained by repeated administration of the
`antibody during the 44 week follow up
`period.90 Endoscopies performed in a subgroup
`of patients in this study demonstrated a clear
`mucosal healing eVect, which correlated with
`the reduction of the clinical disease severity
`score.91 Some patients with perianal fistulas
`experienced remarkable healing in the course
`of the study, and this prompted initiation of a
`separate trial
`to investigate the eYcacy of
`infliximab for this indication. Patients with
`fistulas secondary to Crohn’s disease are com-
`monly treated with immunosuppressive drugs
`(azathioprine and cyclosporine) and anti-
`biotics, but apart from anecdotal reports, no
`medical treatment had been evaluated in a
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`controlled clinical trial. Few reliable data on
`the eYcacy of surgery for fistulas are available,
`but the results are so disappointing that most
`surgeons refrain from curative surgery and only
`perform drainage procedures. Ninety four
`patients were included in the controlled clinical
`infliximab trial for perianal fistulas and were
`infused with infliximab (5 or 10 mg/kg) or pla-
`cebo at 0, 2 and 6 weeks.92 The primary end
`point was healing (no spontaneous or induced
`drainage from the external fistula opening at
`two or more visits) of 50% or more of the fistu-
`las. In significantly more infliximab treated
`patients drainage from the fistulas stopped, and
`in some patients external openings disappeared
`completely (infliximab 5 mg: 68%; placebo
`26%). Moreover, the time to reach the end
`point was significantly shorter in infliximab
`treated patients than in the placebo (that is,
`conventionally treated) group (14 versus 40
`days). Infliximab has also been used to treat a
`small
`number
`of
`patients with
`extra-
`intestinal—“metastatic”—Crohn’s disease. In
`two young women extensive and debilitating
`ulcerations of the perineal area responded very
`well to treatment, and the ulcers remained
`closed (both patients received cyclosporine
`treatment after the infliximab infusion).93
`Infliximab was approved for clinical use in
`active Crohn’s disease in the USA in the autumn
`of 1998, and received a positive advice for the
`European Medicines Evaluation Agency in May
`1999. One of the major issues involved in
`approval was safety. Infusion reactions occur in
`about 6% of patients, which is comparable with
`the rate of infusion reactions associated with
`immunoglobulins or other monoclonal antibod-
`ies, and are usually not severe. In most patients
`infusions can be continued at a slower rate or
`after administration of an antihistamine. Inflixi-
`mab is mouse/human chimeric antibody and
`human-anti-chimeric antibodies are induced in
`13% of patients, and are associated with a
`slightly higher rate of infusion reactions upon
`re-infusion (data on file, Centocor). Some
`patients that were re-infused more than two
`years after the first infusion developed very high
`HACA titres, and this was associated with
`systemic symptoms and signs of serum sickness.
`However, no complement consumption or end-
`organ damage occurred, and the symptoms
`reacted well to corticosteroids or antihistamines
`(data on file, Centocor). High titre HACAs do
`neutralise infliximab and therefore strongly
`interfere with therapeutic eYcacy. To date, no
`definitive advice can be given concerning the
`prevention of HACA development, although
`there are indications that simultaneous treat-
`ment with immunosuppressive drugs lowers the
`HACA rate. Development of malignancies is a
`major complication of most immunosuppressive
`drugs, but at present the incidence of neither
`lymphomas nor solid tumours was found to be
`increased in infliximab treated patients (data on
`file, Centocor). It should be noted that the
`follow up period of most treated patients is still
`short, and a post-treatment surveillance pro-
`gramme has been instituted. TNF♡ is important
`for clearing microbial pathogens and TNF♡
`deficient mice are very susceptible to intracellu-
`
`lar bacterial pathogens. However, when cor-
`rected for a similar follow up period,
`the
`incidence of infectious complications in inflixi-
`mab treated patients does not seem to be higher
`as compared with placebo infused patients, with
`the exception of a slightly higher rate of upper
`respiratory infections (data on file, Centocor).
`Finally, anti-dsDNA antibodies were found in a
`small percentage of infliximab treated Crohn’s
`disease patients. These antibodies tend to be of
`low titre, disappear in most patients, and are not
`associated with symptoms of autoimmune dis-
`ease. It is possible that induction of anti-dsDNA
`antibodies is a direct result of the biological
`activity of infliximab (see below) and therefore
`should be regarded as an “eVect” rather than a
`“side eVect”.
`The clinical experience with other TNF♡
`binding molecules in Crohn’s disease is less
`extensive. A humanised antibody, CDP571, was
`found to have short-term clinical eYcacy in
`patients with active Crohn’s disease, and follow
`up clinical studies are ongoing.94 Completely
`human TNF binding antibodies, and p55
`receptor molecules are currently in (pre)clinical
`development for Crohn’s disease.
`
`How do anti-TNF♡ antibodies work?
`TNF♡ is a potent pro-inflammatory cytokine
`that is able to induce a wide range of secondary
`inflammatory cascades in humans. Many of
`these biological eVects, including the induction
`of cytokines, chemokines and adhesion mol-
`ecules, activation of the coagulation and com-
`plement cascades, and induction of HLA-class
`II molecules on the intestinal epithelium are
`important for mucosal inflammation in Crohn’s
`disease (for review see van Deventer95). On the
`other hand, many other potent pro-inflam-
`matory cytokines (IFN♤, IL1♢) are induced in
`the inflamed intestinal mucosa, and it
`is
`somewhat
`surprising that neutralisation of
`TNF♡ alone has such potent clinical eVects.
`Clinical observations indicate that infliximab
`acts very rapidly (decreases of C reactive protein
`concentration are already observed within days
`after infusion), and the eVects of a clinical infu-
`sion are sustained for 10–12 weeks in most
`patients. In part, these prolonged clinical eVects
`may be explained by the pharmacokinetics of
`the antibody, but data on infliximab tissue con-
`centrations are not available, precluding a
`definitive conclusion. In view of the pivotal role
`of CD4+ T lymphocytes in Crohn’s disease, we
`have focused on the eVects of infliximab on T
`lymphocyte function. Peripheral control of T
`lymphocyte activation and proliferation is
`largely dependent on cytokines (IL10, TGF♢)
`secreted by regulatory T lymphocytes, and on
`induction of apoptosis (review in van Parijs and
`Abbas96). T lymphocyte apoptosis results from
`the activation of death receptors that in turn
`activate intracellular caspases. Some apoptotic
`signals are transduced through alteration of the
`mitochondrial adenodine nucleotide transloca-
`tor (and hence mitochondrial permeability),
`which is controlled by the ratio of two Bcl-2
`family proteins (that is, Bax and Bcl-2), and this
`pathway has been shown to be particularly
`important in T lymphocytes.97–99 Two studies
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`have recently demonstrated that mucosal T
`lymphocytes in Crohn’s disease are resistant to
`induction of apoptosis by various signals and
`this is related to alteration of the Bax/Bcl2
`ratio.61 62 We have investigated the eVects of
`infliximab
`on
`apoptosis
`in CD3/CD28
`stimulated Jurkat T lymphocytes, and observed
`a significant
`increase of
`the ratio of Bax
`(pro-apoptotic) and Bcl-2 (anti-apoptotic). As
`expected, this resulted in increased apoptosis of
`infliximab treated Jurkat cells, but only when the
`cells were previously activated.100 Hence, al-
`though the precise mechanism of apoptosis
`induction remains to be elucidated, these data
`suggested that infliximab, in addition to its anti-
`inflammatory eVects, may function as an “im-
`munotoxin” that specifically targets activated T
`lymphocytes.
`Indeed,
`in infliximab treated
`patients with active Crohn’s disease we found a
`rapid increase (24 hours after the infusion) of
`the number of apoptotic CD3+ lamina propria
`cells, without detectable changes of peripheral
`blood T lymphocyte phenotype or of markers of
`apoptosis.100 These observations would predict
`potential synergism with known inducers of T
`lymphocyte apoptosis (methotrexate), but an-
`tagonism with anti-apoptotic immunosuppres-
`sive drugs (for example, cyclosporine). Hence,
`further characterisation of the eVects of inflixi-
`mab on T lymphocyte function may be helpful
`in designing immunosuppressive combination
`treatments.
`
`Conclusions
`TNF♡ targeting treatments in Crohn’s disease
`have been tremendously boosted by the remark-
`able clinical eYcacy of infliximab. However, dif-
`ferent TNF♡ targeting approaches have diverse
`biological activities, precluding extrapolation of
`the eVects obtained with one reagent to other
`indications. The precise mechanism of action of
`infliximab in Crohn’s disease remains to be elu-
`cidated, but in addition to the expected anti-
`inflammatory activities, recent data strongly
`suggest the involvement of potent eVects on T
`lymphocyte function. Further unravelling of
`these mechanisms may lead to novel therapeutic
`approaches and will aid in designing rational
`combination treatments. Finally, many ques-
`tions remain to be answered,
`including the
`eYcacy of repeated infusions, corticosteroid
`sparing eVects, synergism or antagonism with
`other immunosuppressive drugs and long term
`disease modifying eVects. Several of these ques-
`tions are currently investigated in clinical trials.
`
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