THE AMERICAN JOURNAL OF GASTROENTEROLOGY
`© 2001 by Am. Coll. of Gastroenterology
`Published by Elsevier Science Inc.
`
`Vol. 96, No. 9, 2001
`ISSN 0002-9270/01/$20.00
`PII S0002-9270(01)03267-1
`
`RAPID COMMUNICATION
`Etanercept in the Treatment of Active Refractory
`Crohn’s Disease: A Single-Center Pilot Trial
`Geert D’Haens, M.D., Ph.D., Caroline Swijsen, R.D., Maja Noman, M.D., Liesbeth Lemmens, R.N.,
`Jan Ceuppens, M.D., Ph.D., H. Agbahiwe, M.D., Karel Geboes, M.D., Ph.D., and
`Paul Rutgeerts, M.D., Ph.D.
`Departments of Internal Medicine and Histopathology, University Hospital Gasthuisberg, Leuven, Belgium
`
`OBJECTIVES: Etanercept, an injectable tumor necrosis factor
`(TNF) receptor fusion protein, binds and inactivates human
`TNF and is used in active rheumatoid arthritis. Blocking
`TNF with monoclonal antibodies has also been beneficial in
`Crohn’s disease. We attempted to determine the efficacy and
`safety of etanercept for induction of clinical, endoscopic,
`and histological improvement in patients with moderate to
`severe Crohn’s disease despite standard treatment.
`METHODS: Ten patients with active Crohn’s disease were
`treated with etanercept (25 mg s.c.) twice per week for 12
`wk. Background therapy was kept stable during the trial.
`Crohn’s disease activity index (CDAI),
`Inflammatory
`Bowel Disease Questionnaire, and C-reactive protein levels
`were measured at weeks 0, 2, 4, 8, and 12. Colonoscopies
`were performed before and after therapy in responders;
`endoscopic biopsies were scored for inflammation.
`RESULTS: At week 2 after the start, a clinical response
`(⌬CDAI ⱖ 70) was observed in 6/10 patients (median ⫽
`305 [294 – 418] to 166 [107–392]), with reduction in serum
`C-reactive protein levels (median ⫽ 17.2 [6.8 – 67.2] to 9.1
`[0.9 –17.2] mg/dl). Colonoscopies showed a reduction in
`inflammatory lesions in the four patients who attained re-
`mission (CDAI ⬍ 150), whereas the inflammatory score of
`the biopsies did not decrease significantly. No moderate or
`severe adverse events were observed.
`CONCLUSIONS: Etanercept may be effective in Crohn’s dis-
`ease refractory to standard therapy. (Am J Gastroenterol
`2001;96:2564 –2568. © 2001 by Am. Coll. of Gastroenter-
`ology)
`
`INTRODUCTION
`
`Clinical trials with the chimeric monoclonal IgG1 antibody
`infliximab (Remicade, Centocor, Malvern, PA) and with the
`“humanized” IgG4 antibody CDP 571 (Celltech, Berkshire,
`United Kingdom), both directed against tumor necrosis fac-
`tor (TNF), demonstrated a significant
`improvement of
`symptoms in patients with severe Crohn’s disease refractory
`to standard treatment and closure of fistulas in Crohn’s
`disease enterocutaneous fistulas (1–3). Moreover, both an-
`tibodies have been used successfully to withdraw cortico-
`
`steroids in patients who were corticodependent (4, 5). With
`infliximab, this clinical benefit was accompanied by an
`important degree of endoscopic healing (6) and histological
`improvement (7).
`Side effects with anti-TNF antibodies include transient
`respiratory tract infections, formation of human antichi-
`meric antibodies with associated acute and delayed hyper-
`sensitivity infusion reactions (8), formation of autoantibod-
`ies with rare instances of drug-induced lupus, and a few
`cases of lymphoma (9). The immunogenicity of these treat-
`ments with in many cases partial or complete loss of efficacy
`has stimulated the search for alternative TNF blockers. One
`attractive molecule is the dimeric fusion protein etanercept
`(Enbrel, Immunex, Seattle, WA), with which extensive clin-
`ical experience has been collected in the treatment of rheu-
`matoid arthritis, juvenile rheumatoid arthritis, and psoriatic
`arthritis (10 –14). Etanercept consists of the extracellular
`ligand-binding portion of the human p75 TNF receptor
`linked to the Fc portion of human IgG1. Because it does not
`contain nonhuman material, it is theoretically less immuno-
`genic. The current study was a pilot study to determine the
`efficacy of etanercept in active refractory Crohn’s disease.
`
`MATERIALS AND METHODS
`
`Patient Selection and Study Design
`This open-label study was conducted at a single center and
`was approved by the local ethical committee. All patients
`gave written informed consent. Ten patients aged 18 –70
`were recruited, all having had Crohn’s disease for at least 6
`months, endoscopically and histologically proven. Patients
`had to have active disease with Crohn’s disease activity
`index (CDAI) ⬎ 250 despite at least one other treatment for
`Crohn’s disease including mesalazine, corticosteroids,
`and/or immunosuppressives. Patients using mesalazine had
`to have taken this medication for at least 3 months, with
`stable doses for at least 4 wk. Patients using corticosteroids
`had to be on these drugs for at least 4 wk, with stable dose
`for a minimum of 2 wk. Azathioprine/6-mercaptopurine was
`allowed if taken for at least 6 months with stable dose in the
`last 3 months. Methotrexate was allowed if it had been used
`for at least 3 months with stable doses in the last 4 wk. All
`
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`AJG – September, 2001
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`Etanercept in Crohn’s Disease
`
`2565
`
`of this concomitant treatment was kept stable throughout the
`12-wk treatment period except for corticosteroids, which
`had to be tapered from week 4 after the start of treatment
`according to a standardized schedule in case of a clinical
`response. If patients were using methylprednisolone above 8
`mg/day, it was decreased weekly by 4 mg. Doses of 8 mg
`methylprednisolone/day and lower were decreased by 2
`mg/day every week until stop. If during tapering symptoms
`relapsed, the corticosteroid dose was increased back to 16
`mg/day. This was considered failure of the study treatment.
`Exclusion criteria included pregnancy or inadequate con-
`traception in both men and women for the duration of the
`trial and 6 months thereafter, imminent need for surgery
`because of intra-abdominal abscess, symptomatic stenosis
`or toxic megacolon, concomitant use of nonsteroidal anti-
`inflammatory drugs, positive fecal culture or Clostridium
`difficile toxins, and prior treatment with TNF antibodies or
`blockers.
`
`Treatment
`Treatment consisted of s.c. injections of etanercept (Enbrel)
`(25 mg) given twice per week for 12 wk in addition to the
`ongoing treatment. This medication was provided by the
`manufacturer, Wyeth-Ayerst Laboratories and Immunex
`Corporation (Seattle, WA). Injections were given by a home
`care nurse, the patient’s family doctor, or by the patient his-
`or herself. Instructions were provided as designed by the
`drug manufacturer.
`
`Assessments and Endpoints
`The primary endpoint consisted of clinical response, defined
`as a decrease in the CDAI (15) of at least 70 points. Clinical
`remission represented a CDAI ⬍ 150, as measured at weeks
`2, 4, 8, and 12 after the start of treatment. Additional
`secondary endpoints included withdrawal of corticosteroids,
`endoscopic and histological improvement, improvement in
`the validated quality of life score Inflammatory Bowel Dis-
`ease Questionnaire (IBDQ) (16), and changes in serum
`C-reactive protein (CRP) levels.
`Stool samples were collected during the week before the
`start of treatment for culture and determination of C. difficile
`toxins. During the same period CDAI and IBDQ scores
`were recorded (excluding the day of the first injection).
`Patients used a daily diary system during the whole study
`period for calculations of the CDAI. Female patients under-
`went a urinary pregnancy test on the first day. Blood sam-
`ples for biochemical analysis were also collected on the day
`of the first injection. This analysis included complete blood
`counts, serum CRP levels, electrolytes, serum creatinin and
`urea,
`transaminases, alkaline phosphatase, amylase and
`lipase, and a urine analysis. On that same day patients with
`endoscopically evaluable disease (i.e., colitis or terminal
`ileitis) underwent an ileocolonoscopy after colon prepara-
`tion with an isotonic electrolyte formulation and under mild
`sedation with midazolam and mebeverine. These procedures
`were videotaped. During this examination four biopsies
`were taken in the vicinity of ulcers and used to prepare
`
`sections for both immunohistochemical and routine hema-
`toxylin and eosin staining. Hematoxylin and eosin stainings
`were scored using a standard score for mucosal inflamma-
`tion, which had been published earlier (17). Immunohisto-
`chemistry was performed for four antigens. Antibodies used
`were directed against D-related human leukocyte antigen
`(HLA-DR), one of the major histocompatibility class II
`antigens that can be expressed on epithelial cells of the small
`and large intestine (Becton Dickinson, Mountainview, CA);
`CD68, marking the presence of monocyte/macrophage cells
`(Kp1, Dako, Glostrup, Denmark); TNF, a pivotal proinflam-
`matory cytokine (Innogenetics, Gent, Belgium); and Ki67
`(MiB1, Dako). Ki67 is expressed during the G1, S, G2, and
`M phases of the cell cycle but not in resting noncycling
`cells. It can therefore be used as a marker of proliferation.
`Immunohistochemical stainings were performed using an
`immunoperoxidase technique.
`Follow-up visits were scheduled after 2, 4, 8, and 12 wk
`of therapy and further on every 4 wk until relapse of symp-
`toms. On every occasion CDAI and IBDQ scores were
`calculated and blood was drawn for the same set of bio-
`chemical tests. Adverse events were carefully recorded and
`scored as unrelated or possibly, probably, or definitely re-
`lated. At week 4, tapering of glucocorticosteroids was begun
`as outlined above.
`At week 12 the patients who had a clinical response
`underwent a second colonoscopy after an identical bowel
`cleansing and using the same type of sedation. Patients
`without improvement were not examined again because of
`the high degree of discomfort associated with colonoscopies
`during active disease and the low likelihood of obtaining
`useful information. The change in endoscopic appearance
`was scored using previously published criteria, with com-
`plete mucosal healing meaning complete disappearance of
`any pathological finding, near complete healing a marked
`reduction of mucosal lesions with thickened folds and/or su-
`perficial erosions as the only remaining abnormalities, partial
`healing a significant reduction in the number and size of
`ulcerative lesions, and no healing the persistence or worsening
`of earlier lesions (18). Biopsies were again taken in the vicinity
`of ulcers, similar to the location at the first endoscopy.
`
`Statistical Analysis
`Results of CDAI, IBDQ, and CRP levels are represented as
`medians and means ⫾ SEMs. Differences before and after
`treatment were calculated with a paired two-sided t test
`using NCSS 2000 data analysis programs. ␣was set at 0.05.
`For patients who withdrew prematurely because of ineffi-
`cacy, the last value of the different parameters was carried
`forward for the week 12 analysis.
`
`RESULTS
`
`Study Population
`The individual patient characteristics are represented in Ta-
`ble 1. The mean age of the study group was 29.4 ⫾ 1.9 yr.
`
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`D’Haens et al.
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`Table 1. Patient Characteristics
`Duration of
`Crohn’s Disease
`(yr)
`13
`6
`15
`13
`6
`17
`2
`9
`5
`3
`
`Age
`Sex
`(yr)
`Patient
`F
`31
`1
`F
`32
`2
`F
`28
`3
`F
`30
`4
`F
`32
`5
`M
`37
`6
`F
`26
`7
`F
`25
`8
`F
`25
`9
`M
`28
`10
`C ⫽ colitis; IC ⫽ ileocolitis.
`
`Previous
`Resections
`
`Term ileum
`
`Term ileum
`Term ileum
`Term ileum (twice)
`Term ileum
`
`CDAI
`378
`418
`294
`305
`300
`260
`263
`391
`266
`270
`
`Steroids (Dose of
`Methylprednisolone) Azathioprine Methotrexate Localization
`4 mg/day
`175 mg/day
`IC
`150 mg/day
`C
`150 mg/day
`IC
`125 mg/day
`IC
`150 mg/day
`C
`I
`I
`I
`IC
`IC
`
`100 mg/day
`
`25 mg/wk
`
`32 mg/day
`
`8 mg/day
`
`150 mg/day
`
`The patients had had Crohn’s disease for a mean of 8.9 ⫾
`1.7 yr and had a mean CDAI of 314 ⫾ 19 (range ⫽
`260 – 418) at inclusion. None of the patients had draining
`fistulas. Five patients had had intestinal resections and three
`were using glucocorticosteroids. Five were on stable doses
`of mesalazine (two patients used mesalazine as sole thera-
`py), seven were using azathioprine, and one patient was
`using methotrexate at weekly doses of 25 mg.
`
`Clinical Response
`Of the 10 patients who were treated, six had a decrease in
`CDAI of ⬎70 2 wk after the start of treatment. At week 12,
`7/10 patients demonstrated such response. For all patients
`together, the mean CDAI dropped from 314 ⫾ 19 (260 –
`418) at the start to 219 ⫾ 44 at week 12 (p ⫽ 0.03) (Fig. 1).
`Four patients were in remission (CDAI ⬍ 150) at week 12.
`One patient had to be withdrawn from the study at week 6
`because of lack of response and poor general condition.
`The drop in CDAI from week 0 to week 12 in the
`responders averaged 152 ⫾ 30 (median ⫽ 136, range ⫽
`90 –320). The overall CDAI improvement was not paral-
`leled by a significant improvement in the quality of life: the
`IBDQ increased from a mean of 141 ⫾ 8 at the start to
`151 ⫾ 11 at week 12 (p ⫽ 0.2).
`
`Biochemical Response
`The evolution of serum CRP levels is represented in Figure
`2. Two patients had an initial increase in CRP levels, fol-
`
`lowed by a steady decrease from week 2 onwards. In the
`whole patient group, CRP levels decreased from 4.3 ⫾ 1.3
`mg/dl at the start to 1.4 ⫾ 0.4 mg/dl at week 12 (p ⫽ 0.05).
`In the seven responders, serum CRP levels dropped from
`5.4 ⫾ 1.7 (median ⫽ 6.7 mg/dl, range ⫽ 0.9 –11.6) to 1.4 ⫾
`0.6 mg/dl (median ⫽ 1.2 mg/dl, range ⫽ 0 – 4.6) (p ⫽ 0.02).
`
`Endoscopic, Histological, and
`Immunohistochemical Changes
`Videotapes made before and after treatment (the latter only
`in the patients with a clinical response) were compared. In
`none of the patients was a complete or near complete mu-
`cosal healing observed. A distinct endoscopic improvement
`(partial healing) was only observed in the four patients who
`attained clinical remission. All other patients had no signif-
`icant endoscopic improvement, despite a clinical response.
`The histological activity score for the terminal ileum
`remained largely the same before (median ⫽ 4.3 [2–10])
`and after (median ⫽ 4.8 [7–10]) treatment. The same was
`found for the histology score in the colon, with a median
`score of 5 (4 –12) before treatment and 4.8 (2–10) after. The
`immunohistochemical features showed little or no changes.
`The epithelial expression for HLA-DR and the number of
`CD68 positive cells were identical in samples obtained
`before and 12 wk after administration of etanercept, whereas
`TNF-␣ expression was only mildly reduced (mean number
`of CD68⫹ cells before ⫽ 27.5% and mean number after ⫽
`
`.7 •
`•
`
`550
`500 -H
`450
`400 'T
`350
`300
`250 —
`200
`150
`100 —
`50 —
`0
`
`•
`ce
`
`18 -
`
`16
`
`14 —
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`2
`
`4
`
`8
`
`12
`
`weeks
`
`0
`
`2
`
`4
`
`8
`
`12
`
`weeks
`
`Figure 1. Evolution of CDAI in the 10 patients from week 0 to
`week 12.
`
`Figure 2. Evolution of CRP levels in the 10 patients from week 0
`to week 12.
`
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`AJG – September, 2001
`
`Etanercept in Crohn’s Disease
`
`2567
`
`28% [expressed per 100 lamina propria mononuclear cells]).
`Epithelial labeling with Ki67 was unchanged.
`
`Time to Relapse
`Patients who completed the study were examined every 4
`wk or in case of symptom relapse after discontinuation of
`treatment. Apart from one patient who remained in remis-
`sion longer than 6 months after the last injection, all re-
`sponders reported relapse of Crohn’s-related symptoms
`within 4 wk after discontinuation, with a median time to
`relapse of 3 wk (range ⫽ 1– 4).
`
`Adverse Events
`Etanercept injections were well tolerated. No life-threaten-
`ing or severe adverse events occurred. No febrile or allergic
`reactions were observed. The most common side effect was
`pain at the injection site, which was reported by three
`patients. No changes in kidney or liver function tests were
`detected. Possibly related mild to moderate adverse events
`further included a flulike syndrome (two patients), headache
`(two patients), dizziness (one patient), a burning sensation
`in the eyes (one patient), and mild upper respiratory tract
`infections (three patients).
`
`DISCUSSION
`
`The inflammatory events in Crohn’s disease are largely
`driven by proinflammatory cytokines, of which TNF is
`undoubtedly one of the most pivotal. Monoclonal antibody
`therapy with infliximab has so far been the most successful
`approach to block TNF acitivity. The current study, though
`small and nonblinded, suggests that TNF binding by the
`dimeric fusion protein etanercept may also be an effective
`strategy. Etanercept was first developed for the treatment of
`rheumatoid arthritis, where it is currently being used in
`thousands of patients. From a pathophysiological point of
`view, rheumatoid arthritis and Crohn’s disease share many
`characteristics and are both considered to be Th1-cytokine–
`driven diseases. For this reason it seemed logical to explore
`the efficacy of etanercept in chronic inflammatory bowel
`disease—more specifically, in Crohn’s disease.
`The evolution of the CDAI scores in the current study
`suggests that the onset of action of etanercept was rapid.
`Most patients had a response by week 2 after the start of
`treatment. In rheumatoid arthritis, as well, clinical responses
`appeared within 1 to 2 wk after initiation of therapy and
`nearly always occurred by 3 months (10 –12). The clinical
`improvement in our pilot group was, however, not paral-
`leled by a steep drop in serum CRP levels, as has been
`observed with infliximab in both Crohn’s disease and rheu-
`matoid arthritis (1, 19), but rather by a gradual decrease.
`This may suggest a slower mechanism of action or a lower
`degree of TNF inactivation and offers a possible explanation
`for the limited endoscopic and histological improvement
`after 12 wk of therapy.
`The effect of etanercept seems to disappear rather quickly
`
`after discontinuation of the injections. The time to relapse
`after the 12-wk study period averaged only 3 wk. Two
`possible explanations may be responsible: first, the pharma-
`cokinetics of etanercept, which has a half-life of only 68 ⫾
`19 h (20), and second, the mechanism of action, which
`differs from that of other TNF blockers such as infliximab.
`The latter binds TNF-expressing cells and induces lysis of
`these cells (apoptosis) through complement binding and
`activation (21). Etanercept binds TNF, but evidence that it
`would induce cell lysis is lacking. In the biopsies we ana-
`lyzed we were unable to document decreased expression of
`TNF, the marker of antigen presentation HLA DR, and the
`marker of macrophage activation CD 68. These markers
`were all downregulated in mucosal biopsies from Crohn’s
`patients treated with infliximab (7). Binding TNF by its
`soluble p75 receptor appears insufficient to block its full
`biological activity.
`Although in most controlled clinical trials in Crohn’s
`disease CDAI and the validated quality of life measure
`IBDQ have correlated well, the quality of life in this study
`did not improve as fast as the CDAI would suggest. In
`rheumatoid arthritis, nonetheless, a health assessment ques-
`tionnaire demonstrated improvements of different quality of
`life issues (22). The lack of impact on both endoscopy and
`IBDQ is disturbing. Only a larger and controlled trial can
`clarify this issue and provide a more profound insight into
`the possible benefit of etanercept therapy.
`Besides mild skin reactions at the injection site, etaner-
`cept was well tolerated. Mild to moderate injection site
`reactions (erythema and/or itching, swelling, pain) have
`been reported in 37% of patients in controlled trials and tend
`to decrease in frequency and severity with time (23). Serious
`infections were not observed. With the commercial use of
`etanercept in rheumatoid arthritis, however, several cases of
`lethal sepsis have been reported (Food and Drug Adminis-
`tration warning). All of these patients had been using etan-
`ercept for a prolonged period of time and were also using
`concomitant immunomodulators such as methotrexate. We
`also observed sepsis in one Crohn’s disease patient treated
`with methotrexate and etanercept at our center outside of
`this trial. Data from a clinical trial in sepsis suggest that
`etanercept may increase mortality in patients with estab-
`lished sepsis (24), a risk that could be explained by the fact
`that etanercept binds not only TNF but also lymphotoxin, a
`cytokine that activates lymphocytes when dealing with in-
`fections.
`Immunogenicity is an important issue when biological
`drugs need to be used repeatedly over a prolonged period of
`time. In rheumatoid arthritis patients nonneutralizing anti-
`bodies to etanercept were detected in up to 16% of patients,
`without impairment of clinical response. Human antichi-
`meric antibodies have also been measured in Crohn’s dis-
`ease patients treated with infliximab. Their impact on the
`efficacy of the drug remains to be clarified. In patients with
`delayed hypersensitivity reactions to infliximab, high levels
`of human antichimeric antibodies were measured after ex-
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`D’Haens et al.
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`AJG – Vol. 96, No. 9, 2001
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`posure to the drug following a long “drug holiday,” and in
`these patients the treatment had completely lost its efficacy
`(8). None of these reactions have been reported so far with
`etanercept, possibly because of the treatment schedule with-
`out significant delays between injections.
`In conclusion, this pilot study suggests that etanercept
`may be effective in treating active Crohn’s disease, although
`TNF inactivation may be insufficient to induce genuine
`clinical and endoscopic remission. Controlled trials are cer-
`tainly warranted. The risk of sepsis remains to be clarified.
`
`ACKNOWLEDGMENTS
`
`The authors received support from Wyeth-Ayerst, St-Dav-
`idts, and Immunex (Seattle, WA).
`
`Reprint requests and correspondence: Geert R. D’Haens, M.D.,
`Ph.D., Department of Internal Medicine, University Hospital Gas-
`thuisberg, Herestraat 49, B-3000 Leuven, Belgium.
`Received Mar. 12, 2001; accepted June 26, 2001.
`
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