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`
`470
`
`Gutl997; 40:470-474
`
`Treatment with tumour necrosis factor inhibitor
`oxpentifylline does not improve corticosteroid
`dependent chronic active Crohn's disease
`
`J Bauditz, J H aem ling, M Ortner, H Lochs, A Raedler, S Schreiber
`
`Abstract
`Background-In Crohn's disease, inflam(cid:173)
`mation is presumably sustained by an
`increased production of prointlammatory
`cytokines, in particular tumour necrosis
`factor a
`(TNFa) and interleukin ljl
`(ILl P>. TNFa can induce a host of cellular
`effector events resulting in perpetuation of
`the inflammatory process. In vivo studies
`with anti-TNFa antibody treatment have
`led to impressive clinical results.
`Aims--To investigate whether treatment
`with the TNFa inhibitor oxpentifylline
`results in clinical improvement in corti(cid:173)
`costeroid dependent
`chronic
`active
`Crohn's disease.
`Methods-Sixteen Crohn's disease patients
`received oxpentifylline 400 mg four times a
`day in a four week open label study.
`Results--Blockade ofTNFa production in
`16 patients with corticosteroid dependent
`Crohn' s disease did not improve the clini(cid:173)
`cal disease activity (COAl mean (SEM)
`188·75 (5·65) versus 185·13 (10·87) or the
`endoscopic degree of
`inflammation
`(CDEIS 14·9 (2·87) versus 14·8 (2·27) or
`laboratory parameters.
`Conclusions-In this study, use of the
`TNFa inhibitor oxpentifylline does not
`improve inflammation in Crohn's disease.
`This finding suggests that there may be
`more key mediators than only TNFa in the
`inflammatory process in Crohn's disease.
`(Gut 1997; 40: 470-474)
`
`Keywords: Crohn's disease, intestinal immunity,
`rumou r necrosis factor a, inflammation, oxpentifyllin e.
`
`Recent studies have convincingly demonstrated
`that an increased release of proinflammatory
`cytokines by intestinal lamina propria mono(cid:173)
`nuclear cells is involved in the perpetuation of
`intestinal inflammation in inflammatory bowel
`disease (IBD). •-s Intestinal as well as peripheral
`mononuclear cells are highly activated during
`acute inflammatory bowel disease and hence
`capable of releasing increased amounts of
`several proinflammatory mediators including
`tumour necrosis factor a (TNFa) and inter(cid:173)
`leukin 113 (llr 1 J3). •-a In vitro findings show that
`TNFa is capable of inducing a host of pro(cid:173)
`inflammatory effector events, which are
`thought to be implicated in the pathophysiology
`of iDD. TNFa has been shown to be involved
`in neutrophil
`accumulation,'
`granuloma
`formation,••" upregulation of adhesion mole-
`
`cules on endothelial cells, 12 procoagulant
`effects, 13 induction of increased intestinal per(cid:173)
`meability, 14 and also has direct cyropathic
`effects. 15 TNFa concentrations in serum•• as
`well as stool 17 and intestinal mucosa 1 2 5 were
`found to be raised in patients with active
`Crohn's disease, in comparison with both
`normal contrOls and inactive disease.' 2 18 19
`However, increased transcription and trans(cid:173)
`lation of TNFa is not specific for IBD.20 21 In
`other studies, Isaacs et a/ could not detect
`TNFa messenger RNA in a considerable
`number of biopsy specimens from patiems with
`IDD/ and Hyams et al22 did not report
`increased TNFa values in patients with ffiD.
`The hypothesis that TNFa may be of
`particular importance in the induction and
`perpetuation of intestinal inflammation in IBD
`and consequently suppression ofTNFa should
`improve inflammation in patients with Crohn's
`disease was strongly supported by a series of
`recent therapeutic studiesY 24 Experimental
`treatment of corticosteroid dependent patients
`with active Crohn's disease by a one time
`application of a humanised monoclonal anti(cid:173)
`body directed against TNFa (cA2 lgGl) has
`generated impressive clinical results. Within
`four weeks, clinical and endoscopic inflam(cid:173)
`mation completely resolved in eight of 10
`patients. 24 Other pilot studies using a different
`monoclonal antibody (CDP57 1) directed
`against TNFa could not gen erate such
`impressive results.25 The CDP571 antibody is
`from the lgG4 subclass and is therefore theor(cid:173)
`etically less capable to activate complement in
`comparison with an lgGl antibody.
`If reduction ofTNFa is the exclusive mech(cid:173)
`anism of action of the TNFa cA2 antibody
`treatment, other drugs that also reduce TNFa
`should have similar effects. Oxpentifylline
`(pentoxifylline, PTX), a xanthinoxidase inhibi(cid:173)
`tor, is a strong suppressor of TNFa release by
`a host of different cell populations in vitro as
`well as in vivo.26-33 ln dose between 1200 mgld
`and 2000 mgld, PTX was a strong inhibitor
`of TNFa release in vivo and effective in
`improving TNFa
`releated
`inflammatory
`disease. 27
`' ' The presence of corticosteroids
`29
`-
`potentiates the TNFa inhibitory effect of
`PTX. 34 H owever, as other phosphodiesterase
`inhibitors PTX has additional contrainflam(cid:173)
`matory effects,"' 35 some of which cannot be
`restored by addition ofTNFa in vitro."'
`We treated 16 patients with stable, cortico(cid:173)
`steroid dependent Crohn's disease with PTX
`at a dose of 400 mg four times daily in an open
`label study in which we found no improvement
`
`Charite University
`H ospital, 4th
`Department of
`Medicine/Mucosal
`hnmunology Unit,
`BerUn, Germany
`] Bauditz
`M Ortner
`H Lochs
`S Schrieber
`
`Tabea lnflpmmatory
`Bowd Disease CeDter,
`Hamburg, Germany
`JHaemling
`A Raedler
`Correspondence to:
`Dr S Schreiber,
`Univers.itUtsklinikum
`C haritl:, fV Medi.tin.ischc
`Klinik und Polildinik,
`(Gastroenterology),
`Schumannstr 20121,
`101 17 Bcrlio, ~rmany.
`Accepted for publie:2tion
`28 Augusl 199~
`
`

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`Oxpemifylline in Crohn 's disease
`
`471
`
`of intestinal inflammation or clinical symp(cid:173)
`toms. The discordance of our findings and
`those by Dullemen et al23 24 raises important
`questions regarding the mechanism of cA2 anti
`TNFa antibody treatment.
`
`Methods
`
`PATIENTS
`dependent
`corticosteroid
`active
`Chronic
`Crohn's disease was defined by a Crohn's
`disease activity index (COAl) between 150-250
`and at least 10 mg prednisone daily for a
`minimum of three months. Patients had to have
`at least one active episode requiring acute phase
`treatment}6 in the preceding six months. Diag(cid:173)
`nosis of Crohn's colitis or ileocolitis involving at
`least 30 em of the large bowel had to be
`previously established by radiological, endos(cid:173)
`copic, or clinical criteria/7 or all three. Only
`mesalazine (up to a dose of 1 g thrice daily) and
`corticosteroids were permitted
`as
`anti(cid:173)
`inflammatory treatment and had to be kept
`stable two weeks before the study. Use of
`loperamide or codeine to control diarrhoea was
`permitted and recorded for calculation of the
`than
`COAl. No pain medications, other
`tramadol, nutritional therapy (parenteral, for(cid:173)
`mula diets) or immunosuppressives (within the
`preceding six weeks), were permitted.
`Exclusion criteria were bacterial or parasitic
`pathogens in the patients' stools, a positive
`Clostridium diffici/e toxin test, clinical signs of
`septicaemia, intestinal perforation, megacolon,
`histOry of resections other than an ileocaecal
`resection, signs of stenosis, active fungal or viral
`infection or when it was felt that patients could
`not be maintained stable with their present
`therapeutic regimen for the time of study.
`Patients were also excluded if they had raised
`transaminase activities (>3 times normal),
`hyperbilirubinaemia (>2 times normal), signs
`of renal dysfunction (serum creatinine >33%
`increased) or a serum cholesterol concentration
`of less than 100 mgldl. Informed consent was
`obtained from all patients. The study was given
`approval by the local ethics review committee.
`Of 152 patients with Crohn's disease seen in
`the outpatient clinics, 47 patients with chronic
`active Crohn's disease were screened for
`inclusion in the study. Of these, 31 patients
`were excluded for several reasons: a history of
`
`Clinical data of patients
`
`bowel surgery other than ileocaecal resection
`(9), because it was not expected that their
`corticosteroid treatment would remain stable
`throughout the study (7), clinical signs of
`stenosis ( 6), positive Clostridium difficile toxin
`testing
`(1),
`increased
`transaminases and
`bilirubin (1), and signs of renal dysfunction
`(2). Five patients refused to enter the study.
`The remaining 16 patients (Table) received
`oxpentifylline.
`
`BASEUNE STUDIES AND FOLLOW UP
`A clinical visit was scheduled two weeks before
`the tentative sta.rt of oxpentifylline treatment
`and colonoscopy performed within one week
`before enrolment.
`The ability to perform social functions was
`estimated with a questionnaire according to
`Robinson et al. 38 The social function question(cid:173)
`naire consisted of the following seven ques(cid:173)
`tions: How much do you feel affected by your
`disease: (1) in job related activities, (2) in
`everyday activities in your home, (3) in private
`activities outside your home, (4)
`in your
`general social contacts, (5) in your hobbies/
`spare time, (6) in sexual activities, and (7)
`during sleep. Patients were instructed to mark
`their answer on a horizontal line of7 em length
`with the far left side indicating that the social
`function asked for was not affected and the far
`right side indicated that it was maximally
`affected. Measuring the distance from the far
`left side to the marker the patient set, values
`could be obtained which reached from 0 (fully
`capable of performing the social function) to 7
`(intense suffering from a total disability to
`perform the social function).
`All patients received oxpentifylline (pen(cid:173)
`toxifylline (PTX), Trental, Hoechst AG, Frank(cid:173)
`furt, Germany) at a dose of 400 mg four times
`daily orally. This dose range is established as
`inhibitory for TNF release by trials in AIDS, 28
`bone marrow transplantation27 as well as in
`healthy volunteers.29 Patients were seen two and
`four weeks after start of PTX treatment and at
`each of these time points, laboratory tests were
`performed (including CRP and C reactive
`protein erythrocyte sedimentation rate), a
`physical examination carried out, and the COAl
`calculated. At the four week time point the
`questionnaire, pertaining to the patient's social
`functions/8 was repeated. After four weeks PTX
`
`Corticosteroid
`Duration of
`lkocaecaJ treatment
`Crohn's
`(montlu)
`Pat~nt Age (y) Sex disease (y) CDAI CDELS resection
`
`Prednisone Extraintesti11aJ
`dose (mg) manijesuuwns
`
`Ileum
`Mesalazine inwl'lltd
`
`I
`2
`3
`4
`5
`6
`7
`8
`9
`10
`II
`12
`13
`14
`15
`16
`
`23
`19
`24
`20
`27
`31
`56
`47
`42
`41
`37
`2S
`18
`22
`34
`29
`
`M
`F
`F
`M
`M
`F
`F
`F
`M
`F
`F
`M
`F
`F
`M
`F
`
`4
`7
`5
`2
`8
`5
`24
`17
`2·5
`4 ·5
`II
`9
`2
`1·5
`7
`10
`
`167
`188
`202
`187
`190
`212
`232
`170
`205
`212
`207
`16S
`152
`178
`202
`151
`
`No
`12·4
`15·8 No
`Yes
`14·8
`13·2
`No
`No
`11·7
`No
`13·4
`17·8
`Yes
`16·2
`No
`20·2
`Yes
`No
`15
`13·4
`No
`No
`18·4
`No
`19
`9·6
`No
`No
`11 ·6
`15·4
`No
`
`7
`9
`17
`12
`90
`7
`144
`60
`10
`14
`66
`s
`6
`6
`48
`30
`
`10
`15
`15
`10
`10
`10
`20
`IS
`20
`25
`20
`IS
`10
`10
`IS
`20
`
`arthralgia
`anbritis
`arthralgia
`
`anhralgia
`
`Yes
`Yes
`arthralgia
`erythema nodosum Yes
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`anbritis
`
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`
`

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`
`472
`
`Bauditz, Haemling, Omur, Lochs, Raedler, Schreiber
`
`medication was stopped and a repeat colon(cid:173)
`oscopy was performed (trial end :t3 days).
`increase or
`Patients were
`informed
`to
`decrease their conicosteroid dose in a range of
`:!: 10 mg on demand. Conicosteroid use was
`protocolled in patients diaries. All patients who
`worsened during the trial (by an increase in
`CDAI of >50 points or by physicians global
`assessments), were treated appropriately by
`increasing the daily dose of prednisone. In this
`case PTX was stopped. Patients who stopped
`their medication because of adverse reaction
`(none) or
`treatment failure
`(four), were
`followed up in the same way as those who
`continued
`to receive PTX. The primary
`outcome measure was the induction of clinical
`remission, as defined by decrease of the CD AI
`below 150, but at least by 50 points. Secondary
`outcome measures were changes in CDAI,
`Crohn's disease endoscopic index (CDEIS),l"
`the ability to reduce prednisolone treatment,
`and improvement of social functions.
`
`!:!?
`w
`0 u
`
`20 -
`
`15 -
`
`10 .
`
`s -
`
`300 - B
`
`<(
`0 u
`
`200 -
`
`100 -
`
`n = 16
`
`Start
`
`n = 12
`
`4 Weeks
`
`I:-: \'ITRO CYTOKI!Sc STt;DIES
`Fetal calf sera and pokeweed mitogen were
`purchased from Gibco (Grand Island, NY).
`TN Fa, ILl~' and IL6 ELISA kits were
`obtained from R&D/DPC Biermann (Bad
`Nauheim, Germany). All other chemicals were
`obtained from Sigma if not specified differently.
`Peripheral blood mononuclear cells (PBMNC)
`or peripheral blood monocytes were isolated as
`previously described/0 cultured in the presence
`of pokeweed mitogen ( 1% voVvol, 24 hours),
`and supernatant cytokine values determined in
`duplicate by ELISA.
`
`STATISTICS
`(SEM).
`Results are expressed as mean
`Statistical significance of differences was tested
`by non-parametric Spearman correlation~' or
`the Mann-Whitney U test.
`
`s -
`
`0
`
`- - -- - - -
`14
`Pentoxifylline (days)
`
`- - - - - -
`28
`
`CDEIS and CDAI under treatmem u:ith oxpemifyl/in~.
`CDE!S scores before and after treatmem with oxpemifyllin~
`appeared to be tmchanged. (A) Average CDEIS score.<
`were 14·9 (2·87) before (n=/6) and 14·8 (2·27) after
`treatmem (n=/2). In four patiems oxpemif:yllinc had Ill be
`stopped after tu·o u:eeks became of an increased diseas~
`activity. (8) CDAI scores before treatment with
`oxpemif:ylline ranged berween ISQ-250. During the rna/ w
`significam imprm·emem ~~as obscn·ed.
`
`Serum concentrations of C reactive protein
`(27· 1 (14·7) before treatment versus 35·2
`( I 7 · 5) after treatment) and erythrocyte sedi(cid:173)
`mentation rate (22·8 (4·6) before treatment
`versus 28·6 (5·4) after treatment) did not
`change significantly.
`None of the patients receiving oxpentifylline
`treatment experienced severe side effects.
`
`Results
`
`DISEASE ACTIVITY A:-;D I:-.:FLAMMATIO:-.:
`PARA,"'ETERS
`CDAI scores did not change significantly during
`the treatment period (188·75 (5·65) before
`versus 185·13 (10·87) after treatment; Figure).
`Four patients stopped PTX treatment because
`of increased disease activity. None of the
`patients could discontinue prednisone during
`PTX treatment, five patients reduced pred(cid:173)
`nisone by 5 mg daily, and five patients increased
`prednisone use. Overall, prednisone use on a
`cumulative basis was not changed significantly
`by PTX treatment (15 (4·68) before (n= 16),
`versus 12·5 (2·5) after treatment (n=12)).
`Crohn's disease endoscopic index before
`and after treatment with PTX did not change
`significantly ( 14·9 (2·87) before treatment
`(n= 16) versus 14·8 (2·27) after treatment
`(n=12), Figure). All four patients who had to
`stop PTX treatment because of increased
`clinical activity, did have higher than average
`CDEIS scores at study begin (16·6 mean).
`
`EFFECTS <W PTX 0:-.: T:--IFo PRODL'CTIO:-.:
`In six patienrs TNFcx secretion by peripheral
`monocytes was studied before and at the end
`of PTX treatment (35·8 (13·9) pg/ml before
`treatment versus 13·2 ( 19) after treatment,
`non-significant). All patients had detectable
`TNFcx production before PTX, in five patients
`it decreased below
`the sensitivity range,
`although in two patients values were already at
`the lower detection limit before PTX treat(cid:173)
`ment. In one patient TNFcx release was not
`inhibited by PTX.
`Five healthy volunteers received oxpentifyl(cid:173)
`line 400 mg four times daily for a period of two
`days. Release of TNFcx by I 06 PBMC/ml
`stimulated with lipopolysaccharide ( 1 IJ..g/mJ
`for 24 hours) was significantly suppressed by in
`vivo PTX in comparison with baseline values
`( 1068 (198) before, 251 (122) pg/ml after two
`days oxpentifylline; p=0·008). In contrast,
`secretion of 1Llj3 (324 (66) versus 350 (62)
`pg/ml) and IL6 (2 124 (311) versus 2252 (225)
`pg/ml) did not change significantly.
`
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`
`Oxpemifylline in Crohn 's disease
`
`473
`
`SOCIAL FUNCTION SCORES
`that co(cid:173)
`Social
`function scores showed
`treatment with oxpentifylline did not signifi(cid:173)
`cantly improve the patient's social functions
`except for sleep disturbance (week 0: 3·6
`(0·35) (n= 16), score week 4: 2·4 (0·29)
`(n=12), p=0·017). Upon detailed interviewing
`most patients indicated retrospectively that
`improvement of sleep was due to reduced
`muscle aches and reduced night sweat.
`
`D iscussion
`in Crohn's
`Chronic inflammatory acuvtty
`disease may be sustained by the local release of
`proinflammatory cytokines from
`intestinal
`macrophages and T cells including secretion of
`TNFa, ILl~, and IL6.3 7 13 14 2<>-2 1 As TNFa is
`a potent proinflammatory mediator, which can
`be released by mononuclear phagocytes, acti(cid:173)
`vated T cell subpopulations as well as invading
`granulocytes42 the specific blockade of TNFa
`has been considered a promising approach for
`inflammation. 23 24
`intestinal
`treatment of
`Strong support for this hypothesis has been
`given by experimental treatment of chronic
`corticosteroid dependent Crohn's
`active
`disease with a one time application of a mono(cid:173)
`clonal antibody (cA2) directed against TNFa,
`which induced complete endoscopic and clini(cid:173)
`cal remission in eight of 10 patients within four
`weeks. 23 24 These findings may indicate a
`pivotal role ofTNFa in the pathophysiology of
`intestinal inflammation in Crohn's disease.
`To
`test
`this hypothesis we specifically
`blocked TNFa production by another agent,
`oxpentifylline, which is an established inhibitor
`of TNFa release in vitro as well as in vivo. 26-34
`Oxpentifylline has therefore been used in dose
`from 1200 to 2000 mgld in clinical trials to
`in vivo effects of
`suppress presumable
`TNFa. 27
`-29 33 However, in common with other
`phosphodiesterase inhibitors, PTX may have
`also additional contrainflamrnatory effects
`including a reduction of T lymphocyte cyto(cid:173)
`kine secretion (that is, lFN'Y) in vitro. 30 35
`In contrast with anti-TNFa cA2 antibody
`treatment no effect by PTX could be seen on
`clinical, laboratory or endoscopic activity. With
`the exception of sleep disturbance by the
`disease, none of the social functions assessed
`by a questionnaire improved. However, upon
`a detailed interview most patients indicated
`retrospectively that improvement of sleep was
`due to reduced muscle aches and reduced
`night sweat. These are both symptoms that
`may be attributed to raised TNFa levels.43
`The negative results of PTX treatment
`suggest that the mechanism of anti-TNFa anti(cid:173)
`body treatment (using the monoclonal anti(cid:173)
`body cA223 24 supplied by Centocor, PA, USA)
`in Crohn's disease may not only relate to a
`specific blockade of TNFa secretion. Other
`mechanisms including complement mediated
`lysis of cells expressing membrane bound
`TNFcx44 45 may possibly contribute to
`its
`efficacy. Thus, the cA2 antibody could also
`inhibit mediators apart from TNFa,46 which
`may sustain chronic intestinal inflammation.
`Taken together, our findings and the findings
`
`of Derkx et al23 24 may indicate that there are
`more key mediators than only TNFa in the
`inflammatory process in Crohn's disease.
`It is not known how much suppression of
`TNFa is actually induced in the mucosal
`compartment by either cA2 anti-TNF anti(cid:173)
`body treatment or by PTX. Moreover, the
`possibility exists that a substantial proportion
`of mucosal TNFa originates from T cells, and
`inhibition of TNF production by mucosal T
`cell populations by PTX has not been investi(cid:173)
`gated yet. Finally, although selection criteria
`were similar in both trials, Derxx et al23 24
`investigated in their uncontrolled pilot study a
`more active patient population (as indicated by
`the higher average CDAI)
`than we did.
`Therefore, patients' mucosal TNFa levels may
`have been different between both trials.
`Further studies are necessary to clarify the
`relevance of mucosal TNFa production in the
`pathophysiology of inflammation in Crohn's
`disease. In this pilot trial, oxpentifylline at a
`dose of 400 mg four times daily given over a
`period of four weeks was not effective in
`treating patients with corticosteroid dependent
`chronic active Crohn's disease. Further con(cid:173)
`trolled studies are warranted to examine the
`therapeutic potential of oxpentifylline and
`other TNFa inhibitors in Crohn's disease.
`
`The excellent technical help of Anna Maria Wenner and Stefan
`Eidner is gratefully acknowledged. This work was supported by
`a grant from the Deutsche Forschungsgemeinschaft (SCHR
`51211-2) and by a grant from Syngen Pharma GmbH. Parts of
`the study were presented at the 97"' annual meeting of the
`American Gastroenterological Association in San Francisco
`(Ga.stroenttrology 1996; 110: A861 ).
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