Infliximab for the Treatment of Fistulas in Patients with Crohn's Disease
Daniel H. Present, M.D., Paul Rutgeerts, M.D., Stephan Targan, M.D., Stephen B. Hanauer, M.D., Lloyd Mayer, M.D., R.A. van Hogezand, M.D., Daniel K. Podolsky, M.D., Bruce E. Sands, M.D., Tanja Braakman, M.D., Kimberly L. DeWoody, Ph.D., Thomas F. Schaible, Ph.D., and Sander J.H. van Deventer, M.D., Ph.D.
Background Enterocutaneous fistulas are a serious complicationof Crohn's disease and are difficult to treat. Infliximab, achimeric monoclonal antibody to tumor necrosis factor , hasrecently been developed as a treatment for Crohn's disease.We conducted a randomized, multicenter, double-blind, placebo-controlledtrial of infliximab for the treatment of fistulas in patientswith Crohn's disease.
Methods The study included 94 adult patients who had drainingabdominal or perianal fistulas of at least three months' durationas a complication of Crohn's disease. Patients were randomlyassigned to receive one of three treatments: placebo (31 patients),5 mg of infliximab per kilogram of body weight (31 patients),or 10 mg of infliximab per kilogram (32 patients); all threewere to be administered intravenously at weeks 0, 2, and 6.The primary end point was a reduction of 50 percent or morefrom base line in the number of draining fistulas observed attwo or more consecutive study visits. A secondary end pointwas the closure of all fistulas.
Results Sixty-eight percent of the patients who received 5 mgof infliximab per kilogram and 56 percent of those who received10 mg per kilogram achieved the primary end point, as comparedwith 26 percent of the patients in the placebo group (P=0.002and P=0.02, respectively). In addition, 55 percent of the patientsassigned to receive 5 mg of infliximab per kilogram and 38 percentof those assigned to 10 mg per kilogram had closure of all fistulas,as compared with 13 percent of the patients assigned to placebo(P=0.001 and P=0.04, respectively). The median length of timeduring which the fistulas remained closed was three months.More than 60 percent of patients in all the groups had adverseevents. For patients treated with infliximab, the most commonwere headache, abscess, upper respiratory tract infection, andfatigue.
Conclusions Infliximab is an efficacious treatment for fistulasin patients with Crohn's disease.
Crohn's disease is a chronic inflammatory bowel disease of unknowncause, which is characterized by segmental transmural inflammationand granulomatous lesions of the intestinal mucosa. The diseaseis complicated by the development of fistulas in approximatelyone third of patients.1 Fistulas may be internal (e.g., bowelto bowel, bowel to bladder, or rectovaginal) or enterocutaneous(extending through the abdominal wall or into the perineum).These fistulas rarely heal spontaneously or as a result of drugtreatment and frequently require surgery. According to anecdotalevidence, antibiotics have short-term efficacy in their treatment.Although the use of immunomodulatory agents is associated withimprovement and closure of fistulas, no significant effect hasbeen demonstrated in prospective, placebo-controlled studies.2,3,4
The local production of tumor necrosis factor (TNF-) is thoughtto have a key role in the initiation and propagation of Crohn'sdisease.5,6,7 Production of TNF- in the intestinal mucosa isincreased in patients with Crohn's disease.7,8,9 Neutralizationof TNF- has been suggested as a therapeutic intervention ininflammatory diseases, such as inflammatory bowel disease andrheumatoid arthritis.5,10
Infliximab (formerly known as cA2) is a genetically constructedIgG1 murine–human chimeric monoclonal antibody that bindsboth the soluble subunit and the membrane-bound precursor ofTNF-.11,12 Infliximab inhibits a broad range of biologic activitiesof TNF-, presumably by blocking the interaction of TNF- withits receptors, and it may also cause lysis of cells that produceTNF-.12,13 Infliximab has been found to be efficacious and safein the treatment of moderate-to-severe Crohn's disease in severalclinical trials.14,15,16,17 Anecdotal reports of the closureof fistulas in these trials prompted us to evaluate the efficacyof infliximab in healing enterocutaneous fistulas.
Methods
Patients
We enrolled patients who were 18 to 65 years of age and whohad single or multiple draining abdominal or perianal fistulasof at least three months' duration as a complication of Crohn'sdisease that had been confirmed by radiography, endoscopy, orpathological examination. Patients could receive concomitanttherapy. Acceptable regimens were aminosalicylates at a dosagethat had been stable for more than four weeks before screening;oral corticosteroids at a dosage of 40 mg or less per day thathad been stable for more than three weeks; methotrexate givenfor at least three months at a dosage that had been stable formore than four weeks; azathioprine or mercaptopurine given forat least six months at a dosage that had been stable for morethan eight weeks; and antibiotics at a dosage that had beenstable for more than four weeks. If patients were not currentlyreceiving treatment with any of these medications, they hadto have discontinued therapy at least four weeks before enrollment.Patients treated concurrently with cyclosporine were excludedfrom the study. Treatment with investigational agents or theuse of any medication to reduce the concentration of TNF- wasnot allowed within three months before enrollment. Additionalexclusion criteria were other complications of Crohn's disease,such as current strictures or abscesses; the presence of a stomacreated less than six months before enrollment; a history ofallergy to murine proteins; and previous treatment with infliximab.Men and women with reproductive potential were required to usean acceptable form of birth control throughout the study andfor six months after the final infusion.
One hundred twenty patients were screened at 12 centers in theUnited States and Europe, of whom 94 were enrolled. The protocolwas approved by the institutional review boards and ethics committeesat all sites, and all patients gave written informed consentbefore enrolling in the study.
Protocol
The screening procedures included a physical examination, routinelaboratory analyses, assessment of the severity of disease accordingto the Crohn's Disease Activity Index and, for patients whohad perianal disease at base line, a Perianal Disease ActivityIndex. The Crohn's Disease Activity Index incorporates eightrelated variables: the number of liquid or very soft stoolsper day, the severity of abdominal pain or cramping, generalwell-being, the presence or absence of extraintestinal manifestationsof disease, the presence or absence of an abdominal mass, theuse or nonuse of antidiarrheal drugs, the hematocrit, and bodyweight.18 These items yield a composite score ranging approximatelyfrom 0 to 600; scores below 150 indicate remission, whereasscores above 450 indicate severe illness. The Perianal DiseaseActivity Index incorporates five elements: the presence or absenceof discharge, pain or restriction of activities of daily living,restriction of sexual activity, the type of perianal disease,and the degree of induration, yielding a composite score rangingfrom 0 to 20, with higher scores indicating more severe disease.19All fistulas had to be distinctly identifiable; drawings aswell as photographs were used to document the sites of disease.
Within seven days of screening, eligible patients were randomlyassigned to receive one of three treatments: placebo, 5 mg ofinfliximab per kilogram of body weight, or 10 mg of infliximabper kilogram, all to be given intravenously at weeks 0, 2, and6. Randomization was performed by an independent organization(PPD Pharmaco, Austin, Tex.), using a stratified treatment assignment20with the investigational site and the number of fistulas (oneor more than one) as the stratification variables. Patientswere enrolled from May 30 through October 1, 1996.
Infliximab was administered intravenously. Infliximab (ChimericA2 [cA2] IgG, Centocor, Malvern, Pa.) was supplied as a lyophilizedsolid containing 250 mg of cA2 IgG, 2.5 g of sucrose, 61.0 mgof dibasic sodium phosphate dihydrate, 21.7 mg of monobasicsodium phosphate monohydrate, and 2.5 mg of polysorbate 80 ina 100-ml vial for reconstitution in 50 ml of sterile water.The medication was added to the diluent directly from the 100-mlvial with a 15-µm filter, then infused slowly over a two-hourperiod.
The placebo preparation was supplied as a lyophilized solidcontaining 25 mg of human serum albumin, 2.5 g of sucrose, 61.0mg of dibasic sodium phosphate dihydrate, 21.7 mg of monobasicsodium phosphate monohydrate, and 2.5 mg of polysorbate 80 ina 100-ml vial for reconstitution in 50 ml of sterile water.The placebo was identical in appearance to the infliximab solution.
After the first infusion of study medication, patients returnedfor clinical and laboratory assessments at weeks 2, 6, 10, 14,and 18. Blood samples were drawn at each study visit and atweeks 26 and 34 to determine the serum concentration of infliximab.
Evaluation of Efficacy
The primary efficacy end point was defined a priori as a reductionof 50 percent or more from base line in the number of drainingfistulas observed at two or more consecutive study visits. Treatmentwas considered to have failed in patients who had changes inmedication that were not permitted in the protocol, who underwentsurgery related to Crohn's disease, or who did not return forfollow-up visits.
The primary end point was based on the investigators' physicalevaluation of the patient; a fistula was considered to be closedwhen it no longer drained despite gentle finger compression.Draining fistulas of less than three months' duration at baseline were excluded from the primary analysis. In order for apatient to reach the primary end point, a minimum of 21 daysbetween consecutive visits was required.
Secondary analyses of efficacy evaluated the number of patientswith a complete response (defined as the absence of any drainingfistulas at two consecutive visits), the length of time to thebeginning of a response, and the duration of the response. Changesin scores on the Crohn's Disease Activity Index and the PerianalDisease Activity Index were also evaluated.
Evaluation of Safety
Safety was assessed in terms of the incidence of adverse eventsand changes in vital signs and routine laboratory measures.Patients were monitored for adverse events during each infusionand at each study visit.
Immunologic Evaluation
We conducted assays to detect the formation of antinuclear antibodies,antibodies against double-stranded DNA, and human antichimericantibodies. Antinuclear antibodies were measured by means ofa standard immunofluorescence technique in HEp-2 cells, witha screening dilution of the sample of 1:40 (negative resultswere defined as less than 1:40). Patients who were positivefor antinuclear antibodies were evaluated for antibodies againstdouble-stranded DNA with the Crithidia luciliae immunofluorescencetechnique and a screening dilution of 1:10. Antibodies againstdouble-stranded DNA were measured in patients with positiveresults by means of the Farr radioimmunoassay. Patients wereconsidered positive for antibodies against double-stranded DNAif they had positive results on both the C. luciliae immunofluorescenceassay and the Farr radioimmunoassay. Human antichimeric antibodieswere measured with use of a double-antigen enzyme immunoassay.
Statistical Analysis
The primary analysis was performed according to the intention-to-treatprinciple and included all patients who were screened and randomlyassigned to treatment. The analysis was performed in two stages.We performed the Mantel–Haenszel chi-square test for alinear dose response in the proportion of patients in whom theprimary end point occurred. If the result was significant atan alpha level of 0.05, Fisher's exact test was then used tocompare the proportion of patients achieving the primary endpoint in each of the two infliximab groups with that in theplacebo group. Odds ratios were used to assess the consistencyof benefit of infliximab treatment in subgroups of patients.
Analysis of the proportion of patients who had a complete responsewas performed with the same methods used for the analysis ofthe primary end point. Continuous variables (e.g., scores onthe Crohn's Disease Activity Index and Perianal Disease ActivityIndex) were compared by analysis of variance of the van derWaerden normal scores. For patients who discontinued regularlyscheduled follow-up, underwent a surgical procedure, or hada change in medication that was not permitted by protocol, themeasurements from the last evaluation were carried forward.All reported P values are two-sided.
Results
Ninety-four patients were randomly assigned to treatment withinfliximab or placebo. Demographic and clinical characteristicsand rates of use of concomitant medications were similar inall treatment groups at base line (Table 1). Six patients discontinuedtreatment (four in the placebo group and two treated with infliximab);all had received two of the three scheduled infusions. The reasonsfor withdrawal were lack of efficacy (three patients in theplacebo group), administrative reasons (one in the placebo group),withdrawal of consent (one patient assigned to 5 mg of infliximabper kilogram), and adverse events (one patient treated with10 mg of infliximab per kilogram).
Table 1. Base-Line Characteristics of the Patients, According to Study Group.
Efficacy
With respect to the primary efficacy end point, response rateswere significantly greater among the patients receiving infliximab(68 percent in the group assigned to 5 mg per kilogram and 56percent in the group receiving 10 mg per kilogram) than in theplacebo group (26 percent; P=0.002 and P=0.02, respectively)(Table 2). Response rates in the two infliximab groups werenot significantly different (P=0.35). The results of treatmentare summarized in Table 2. Photographs of the healing of fistulasover time in two patients are shown in Figure 1. There was acomplete response, defined as the absence of any draining fistulas,in 55 percent of the patients treated with 5 mg of infliximabper kilogram, in 38 percent of those treated with 10 mg perkilogram, and in 13 percent of patients receiving placebo (P=0.001and P=0.04, respectively). Complete responses occurred bothin patients with single fistulas and in those with multiplefistulas; of the 29 infliximab-treated patients with a completeresponse, 15 had a single fistula and 14 had multiple fistulasat base line.
Figure 1. Closure of an Abdominal Fistula in a 60-Year-Old Man and a Perianal Fistula in a 42-Year-Old Man.
Both patients received 5 mg of infliximab per kilogram.
In patients who reached the primary end point, the length oftime to the beginning of a response was calculated as the numberof days from the initial infusion to the first of the two ormore consecutive visits at which this end point was observed.The median time to the onset of a response (Table 2) was shorteramong patients treated with infliximab (two weeks) than amongthose given placebo (six weeks). The duration of the responsewas defined as the maximal period during which the patient hada reduction of 50 percent or more in the number of drainingfistulas at consecutive visits. The median duration of responsewas approximately three months in patients who reached the primaryend point (Table 2). Changes over time in the scores on theCrohn's Disease Activity Index and the Perianal Disease ActivityIndex are shown in Table 2, according to treatment group.
A consistent benefit of infliximab treatment was observed forall demographic subgroups we evaluated (Table 3). A significantbenefit of treatment was still evident when the analyses wereadjusted for sex or prior bowel resection with logistic regression(P=0.001, data not shown). Significantly more of the patientswith single fistulas who were treated with infliximab reachedthe primary end point than patients assigned to placebo (52percent vs. 8 percent, P=0.02); the same was true for patientswith multiple fistulas (71 percent vs. 39 percent, P=0.03).In addition, infliximab was consistently beneficial regardlessof concomitant therapy (e.g., corticosteroids, mercaptopurineor azathioprine, or antibiotics).
Table 3. Results of Treatment According to Selected Variables.
Safety
All 94 patients were evaluated for safety. The percentage ofpatients with adverse events was the same for the group assignedto receive 5 mg of infliximab per kilogram and that assignedto placebo (65 percent); there was a trend toward more adverseevents among the patients assigned to receive 10 mg of infliximabper kilogram (84 percent, P=0.09). The most frequently reportedadverse events among patients treated with infliximab were headache,abscess, upper respiratory tract infection, and fatigue (Table 4).One patient in the group receiving 10 mg of infliximab perkilogram discontinued treatment because of pneumonia, whichdeveloped 22 days after the second infusion. The symptoms resolvedwithin a week with antibiotic treatment. Altogether, five patientshad serious adverse events: four assigned to receive 10 mg ofinfliximab per kilogram and one assigned to receive 5 mg perkilogram. In the 10-mg group, these events were chest pain andpneumonia (in the patient who discontinued treatment), intestinalobstruction, abscess of the arm and leg (furunculosis), andanal abscess. In the patient in the 5-mg infliximab group, ureteralobstruction developed after the third infusion. In four of thepatients receiving infliximab (6 percent), adverse events occurredduring an infusion or within two hours after the end of theinfusion, with some patients having multiple adverse reactions;these adverse events were mild dizziness in two patients, subfebriletemperature elevation in two, headache in one, and chest painwith flushing in two. There were no consistent differences inroutine laboratory values between the infliximab and placebogroups. No deaths occurred during the study period.
Table 4. Adverse Events That Occurred in at Least 10 Percent of Patients in Any Treatment Group.
Immunologic Results
Antibodies against double-stranded DNA were detected in eightpatients treated with infliximab (13 percent); one patient remainedpositive for these antibodies at the last evaluation. None hadsymptoms suggestive of lupus erythematosus. Serum samples werecollected both before and after treatment from 92 patients andassayed for human antichimeric antibodies. Three tested positivefor human antichimeric antibodies, all at a titer of 1:10. Thirteenpatients had measurable concentrations of infliximab in allpost-treatment samples and therefore could not be evaluated.None of the adverse events in the patients who were positivefor human antichimeric antibodies were suggestive of a sensitivityreaction.
Discussion
Closure of fistulas is rare in patients with Crohn's diseasewho are receiving standard therapy, such as 5-aminosalicylatesor corticosteroids. Several antibiotics have shown promise forthe healing of fistulas in Crohn's disease,21,22,23 but theirefficacy has not been established in controlled clinical trials.Immunomodulatory agents have been used to treat fistulas, withsome success. In one uncontrolled study, fistulas closed inabout one third of patients treated with methotrexate.24 Small,uncontrolled studies have demonstrated that intravenous cyclosporineinduces the closure of fistulas; however, patients relapsedwhen switched to oral cyclosporine.4,25 A double-blind, placebo-controlledstudy3 suggested that mercaptopurine was more effective thanplacebo in the treatment of fistulas in patients with Crohn'sdisease; however, the study had too few patients for the statisticalsignificance of this finding to be assessed. In addition, approximatelythree months was required for a response to appear in patientstreated with mercaptopurine.
In our study, we found a significant reduction in the numberof draining fistulas in patients with Crohn's disease, as comparedwith the number at base line, after two or three infusions ofinfliximab at doses of 5 or 10 mg per kilogram. The effect oftreatment with infliximab became evident rapidly — inabout two weeks — and lasted for a median of three months;a complete response (defined as the absence of draining fistulas)occurred in 46 percent of patients treated with infliximab,as compared with 13 percent of the placebo group (P=0.001).The beneficial effect of infliximab did not appear to be dose-related;patients treated with 5 mg of infliximab per kilogram had ahigher rate of response than those treated with 10 mg per kilogram(68 percent vs. 56 percent).
The frequency of adverse events was the same in the placebogroup and the group assigned to 5 mg of infliximab per kilogram;there was a trend toward more adverse events in the group assignedto 10 mg of infliximab per kilogram. Eight patients treatedwith infliximab (13 percent) had low levels of antibodies againstdouble-stranded DNA. In all but one, these antibodies disappearedby the end of the study. The clinical significance of theseserologic findings is uncertain; none of the patients had symptomssuggestive of lupus erythematosus. In an earlier trial,17 aduodenal lymphoma developed in one patient with a 30-year historyof Crohn's disease. The association of this event with infliximabis uncertain, since the incidence of lymphoma is increased inchronic Crohn's disease.26
Some issues remain to be addressed regarding the use of infliximabin patients with Crohn's disease that is complicated by fistulas.These include the use of infliximab as an effective corticosteroid-sparingagent, the long-term toxicity of the regular or intermittentuse of infliximab, and the best timing for the administrationof infliximab. The majority of patients in this study had chronicallyactive disease and had previously received several therapies,including immunosuppressive agents. The efficacy of a regimenbased on infliximab as a first-line therapy to induce earlyclosure of fistulas, with mercaptopurine or azathioprine reservedfor long-term maintenance after fistulas have healed, needsfurther investigation.
In conclusion, we found that infliximab was efficacious in thetreatment of enterocutaneous fistulas complicating Crohn's disease.Our results support the use of an initial dose of 5 mg per kilogram,with subsequent identical doses given two and six weeks later.
Dr. Hanauer, Dr. Podolsky, and Dr. Sands have served as paidconsultants to Centocor. Dr. Present and Dr. Hanauer have receivedhonorariums from Centocor for lectures. Dr. Mayer owns stockin Centocor.
Source Information
From Mount Sinai Medical Center, New York (D.H.P., L.M.); University Hospital, Leuven, Belgium (P.R.); Cedars Sinai Medical Center, Los Angeles (S.T.); the University of Chicago, Chicago (S.B.H.); Leiden University Medical Center, Leiden, the Netherlands (R.A.H.); the Gastrointestinal Unit and Center for Inflammatory Bowel Diseases, Massachusetts General Hospital and Harvard Medical School, Boston (D.K.P., B.E.S.); Centocor, Malvern, Pa. (T.B., K.L.D., T.F.S.); and the Academic Medical Center, Amsterdam (S.J.H.D.). Other participants in the study are listed in the Appendix.
Address reprint requests to Dr. Present at 12 E. 86th St., New York, NY 10028-0517.
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Appendix
In addition to the authors, the following participated in thestudy: Duke University Medical Center, Durham, N.C. —J. Onken; Methodist Hospital, Houston — A.L. Buchman;Thomas Jefferson University Hospital, Philadelphia — A.J.DiMarino; Saint Mark's Hospital, London — M. Kamm; andLeeds General Infirmary, Leeds, United Kingdom — D.M.Chalmers.
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, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. 
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