Influence of Immunogenicity on the Long-Term Efficacy of Infliximab in Crohn's Disease
Filip Baert, M.D., Maja Noman, M.D., Severine Vermeire, M.D., Ph.D., Gert Van Assche, M.D., Ph.D., Geert D' Haens, M.D., Ph.D., An Carbonez, Ph.D., and Paul Rutgeerts, M.D., Ph.D.
Background Treatment with infliximab, a chimeric monoclonalIgG1 antibody against tumor necrosis factor, can result in theformation of antibodies against infliximab. We evaluated theclinical significance of these antibodies in patients with Crohn'sdisease.
Methods In a cohort of 125 consecutive patients with Crohn'sdisease who were treated with infliximab infusions, we evaluatedthe concentrations of infliximab and of antibodies against infliximab,clinical data, side effects (including infusion reactions),and the use of concomitant medications before and 4, 8, and12 weeks after each infusion.
Results A mean of 3.9 infusions (range, 1 to 17) per patientwere administered over a mean period of 10 months. Antibodiesagainst infliximab were detected in 61 percent of patients.The presence of concentrations of 8.0 µg per milliliteror greater before an infusion predicted a shorter duration ofresponse (35 days, as compared with 71 days among patients withconcentrations of less than 8.0 µg per milliliter; P<0.001)and a higher risk of infusion reactions (relative risk, 2.40;95 percent confidence interval, 1.65 to 3.66; P<0.001). Infliximabconcentrations were significantly lower at four weeks amongpatients who had had an infusion reaction than among patientswho had never had an infusion reaction (median, 1.2 vs. 14.1µg per milliliter; P<0.001). Patients who had infusionreactions had a median duration of clinical response of 38.5days, as compared with 65 days among patients who did not havean infusion reaction (P<0.001). Concomitant immunosuppressivetherapy was predictive of low titers of antibodies against infliximab(P<0.001) and high concentrations of infliximab four weeksafter an infusion (P<0.001).
Conclusions The development of antibodies against infliximabis associated with an increased risk of infusion reactions anda reduced duration of response to treatment. Concomitant immunosuppressivetherapy reduces the magnitude of the immunogenic response.
Infliximab (Remicade, Centocor), a chimeric monoclonal IgG1antibody against tumor necrosis factor, has been approved forthe treatment of moderate-to-severe Crohn's disease in patientswho have an inadequate response to conventional therapy andfor the management of enterocutaneous fistulas. A single intravenousinfusion induced a response at four weeks in 50 to 81 percentof patients with refractory luminal disease and induced remissionin 25 to 48 percent.1 The response can be maintained with repeatedinfusions.2 In patients with fistulizing disease, four weeksafter the last of three infusions, at weeks 0, 2, and 6, 38to 55 percent of fistulas had completely closed, and the medianduration of response was 90 days.3 Clinicians often re-treatpatients with infliximab after a relapse.
Infliximab therapy can result in the formation of antibodiesagainst infliximab. The presence of these antibodies has beenassociated with infusion reactions in 6.9 to 19 percent of patients.4,5,6,7,8,9These antibodies may also have shortened the duration of effectof repeated infliximab treatments. We studied the relation betweenantibodies against infliximab and postinfusion infliximab concentrations,the clinical effect of infliximab, and infusion-related sideeffects. In addition, we investigated risk factors for the formationof antibodies against infliximab.
Methods
Patients
We studied 125 consecutive patients with refractory luminalor fistulizing Crohn's disease who were starting treatment withinfliximab between December 1998 and July 2000. All patientssigned an informed-consent form describing procedures for safetyfollow-up. The study was approved by the institutional reviewboard.
Patients were treated for active luminal disease with a singleintravenous infusion of 5 mg of infliximab per kilogram of bodyweight and for draining fistulas with a series of three infusionsof 5 mg per kilogram, at weeks 0, 2, and 6. If a patient hada response, therapy was repeated on relapse of the disease.The decision to re-treat was made by an experienced clinicianwhen relapse was apparent as a result of increased diarrhea,increased abdominal pain, and decreased well-being. Infusionswere administered under close supervision by a specially trainednurse at an infusion facility. An infusion reaction was definedas any significant adverse event that occurred during the infusionor within two hours afterward.10 When an infusion reaction occurred,the infusion was stopped and restarted at a slower rate. Ifthe symptoms recurred, 100 mg of intravenous hydrocortisoneand 50 mg of intramuscular promethazine were given. This regimenwas then given prophylactically 30 minutes before each subsequentinfusion. Concomitant medications including immunosuppressiveagents and corticosteroids were used as indicated to controlbowel disease. Treatment with immunosuppressive agents consistedof azathioprine (2.0 to 2.5 mg per kilogram per day), mercaptopurine(1.0 to 1.25 mg per kilogram per day), or methotrexate (15 mgintramuscularly once weekly) for a median of 9.5 months (range,2 to 84) before infliximab therapy began.
Evaluations
All patients were evaluated before and every four weeks aftereach infusion, and side effects, including early reactions (infusionreactions) and late reactions (rash, arthralgia, fatigue, myalgia,and influenza-like symptoms), were recorded. Concentrationsof infliximab and antibodies against infliximab in serum weremeasured at each visit and before each infusion. Each serumsample was assessed for infliximab and antibodies against infliximabin duplicate in a blinded fashion by Prometheus Laboratories;the values reported are the means. The infliximab assay wasa microplate enzyme-linked immunosorbent assay in which infliximabbound to immobilized tumor necrosis factor is detected withhorseradish peroxidase–conjugated antihuman IgG (Fc-specific).The cutoff value, which was based on the mean (+3 SD) valuein serum samples from 40 patients who had never received infliximab,was 1.40 µg per milliliter. Concentrations below the cutoffvalue are reported as negative. In the case of 140 samples,concentrations greater than 20 µg per milliliter werereported as 21 µg per milliliter.
The assay for antibodies against infliximab was a microplateenzyme-linked immunosorbent assay based on the double-antigenformat in which infliximab is used both during the solid phaseto capture antibodies against infliximab and during the biotinylateddetection phase with Neutravidin–horseradish peroxidase.The value is reported in micrograms per milliliter on the basisof calibrations made with affinity-purified polyclonal rabbitantimouse IgG F(ab'). The mean cutoff value in serum samplesfrom 40 patients who had never received infliximab was 1.69µg per milliliter. Antibodies against infliximab werereported as negative when the concentration was less than 1.69µg per milliliter and the serum infliximab concentrationwas less than 1.40 µg per milliliter and as indeterminatewhen the concentration was less than 1.69 µg per milliliterbut the infliximab concentration was 1.40 µg per milliliteror greater. Because infliximab interferes with the assay, thesevalues cannot be conclusively determined. The antibody testwas considered to be positive when the concentration exceeded1.69 µg per milliliter and the infliximab concentrationwas less than 1.40 µg per milliliter.
Statistical Analysis
Patients were included in efficacy analyses if they had an initialclinical response and if they required further infusions foractive luminal disease. Patients who underwent surgery and patientsin whom the interval between infusions exceeded 20 weeks wereexcluded from the analysis. Patients with fistulas were includedonly if they required repeated infusions for active luminaldisease after the initial three infusions. All serum sampleswith an indeterminate value for antibodies against infliximabwere excluded from the analyses of antibodies against infliximab.The use of azathioprine, mercaptopurine, or methotrexate wasconsidered as a single risk factor.
We used SAS software (version 6.12, SAS Institute) for all statisticalanalyses. Possible associations between two binary variableswere assessed with use of the relative risk and corresponding95 percent confidence interval. Analysis of variance was usedfor the analysis of continuous outcome variables with discreteexploratory variables. The Tukey multiple-comparison procedurewas used to evaluate the statistical significance of a set ofmultiple comparisons. We used a generalized linear model toevaluate the simultaneous effect of two or more factors on theresponse variables. In some subgroups, we applied a nonparametricprocedure (nonparametric one-way analysis), because of the smallnumber of patients. The Kruskal–Wallis test was used toevaluate whether groups came from the same population. To investigatethe relation between the duration of response and the concentrationof antibodies against infliximab as well as infliximab concentrations,we used multiple linear regression analysis. The manufacturerof infliximab had no input into the design of the study, dataanalysis, or manuscript preparation. The analysis of the manufacturer'ssafety data was performed independently by the authors.
Results
The characteristics of the 125 patients and their concomitanttherapies are shown in Table 1. The median follow-up was 36months (range, 25 to 48). Thirty-eight of the 125 patients (30percent) received treatment for a fistula; and a total of 89patients (71 percent) had a response to infliximab treatment.
Table 1. Demographic Characteristics of the 125 Patients.
Antibodies against Infliximab
At base line no patient tested positive for antibodies againstinfliximab. After the fifth infusion, 76 patients (61 percent)had detectable antibodies (Figure 1A). The incidence did notincrease further with repeated infusions. The serum concentrationsof antibodies against infliximab had two clusters that couldbe separated with the use of 8.0 µg per milliliter asa cutoff value: 46 of the 125 patients (37 percent) had a titerof 8.0 µg per milliliter or greater. Patients who weretaking immunosuppressive agents had a lower incidence of antibodiesthan patients who were not taking immunosuppressive agents:43 percent (24 of 56), as compared with 75 percent (52 of 69)(P<0.01). Immunosuppressive agents also protected againsthigh titers of antibodies. Among patients taking immunosuppressiveagents, as compared with those who were not taking immunosuppressiveagents, the relative risk of antibody concentrations of 8.0µg per milliliter or greater was 2.40 in the group withoutfistulas (95 percent confidence interval, 1.56 to 3.65; P<0.001)and 2.85 in the group with fistulas (95 percent confidence interval,1.54 to 5.25; P<0.001). Among patients who were not takingimmunosuppressive agents, the median concentration of infliximabantibodies was 13.8 µg per milliliter in the group withoutfistulas (95 percent confidence interval, 7.9 to 16.2) and 21.4µg per milliliter in the group with fistulas (95 percentconfidence interval, 13.2 to 24.5). Among patients who weretaking immunosuppressive agents, the concentration of antibodiesagainst infliximab was 1.3 µg per milliliter (95 percentconfidence interval, 0.6 to 3.2) in the group without fistulasand 1.5 µg per milliliter (95 percent confidence interval,0.4 to 8.8) in the group with fistulas (P<0.001 by the Kruskal–Wallistest) (Figure 2).
Figure 1. Cumulative Incidence of Antibodies against Infliximab (Panel A) and of Infusion Reactions (Panel B) in the Study Cohort.
Antibody concentrations were measured at base line and at regular intervals during follow-up, beginning after the first infusion among patients with luminal disease and the first series of three infusions among patients with fistulizing disease and before each subsequent infliximab infusion.
Figure 2. Relation between Concentrations of Antibodies against Infliximab and the Use of Immunosuppressive Therapy among Patients without Fistulas (Panel A) and Patients with Fistulas (Panel B).
The box plots show the median values and the first and third quartiles in each group. The T bars represent the rest of the data with a maximum of 1.5 times the interquartile range. Concentrations of antibodies against infliximab were significantly lower (P<0.001) among patients who were taking azathioprine, mercaptopurine, or methotrexate than among patients who were not receiving immunosuppressive therapy.
We found no association between antibodies against infliximaband sex, the location of disease, smoking status, or the useof mesalamine or corticosteroids at the time of an infliximabinfusion. There was a weak positive relation between the three-infusionregimen (used at 0, 2, and 6 weeks in patients with a fistula)and the development of antibodies against infliximab (P=0.04).
The cumulative incidence of infusion reactions was 27 percent.No reactions occurred during the first infusion, but the incidenceincreased during the subsequent infusions (Figure 1B). Therewas a strong relation between the concentration of antibodiesagainst infliximab and the occurrence of an infusion reaction.The median concentration was 20.1 µg per milliliter (95percent confidence interval, 3.0 to 22.6) at the time of a firstinfusion reaction, as compared with 3.2 µg per milliliter(95 percent confidence interval, 1.6 to 4.9) among patientswithout an infusion reaction (P<0.001) (Figure 3A). Concentrationsof 8 µg per milliliter or higher predicted a higher riskof infusion reactions (relative risk, 2.40; 95 percent confidenceinterval, 1.65 to 3.66; P<0.001). Influenza-like reactions,arthralgia, rashes, fatigue, and myalgia were not related tothe development of antibodies against infliximab.
Figure 3. Concentrations of Antibodies against Infliximab Immediately before an Infliximab Infusion (Panel A), Infliximab Concentrations Four Weeks after the Infusion (Panel B), and the Duration of Response (Panel C), According to the Occurrence of Infusion Reactions.
Box plots show the median values and the first and third quartiles in each group. The T bars represent the rest of the data with a maximum of 1.5 times the interquartile range. The median antibody concentration in the group with no infusion reactions differed significantly (P<0.001) from the median values in the three other groups. The median infliximab concentration in the group with no infusion reactions and the group with no further reactions after prophylactic therapy differed significantly (P<0.001) from the median values in the other two groups. The median number of days until the subsequent infusion in the group with no infusion reactions differed significantly (P<0.001) from the median values in the three other groups.
We chose the time to the next infusion as a measure of the durationof response. There was a clear negative relation between theconcentration of antibodies against infliximab and the durationof the response to infliximab (P<0.001). Antibody concentrationsof 8.0 µg per milliliter or greater were predictive ofa shorter duration of response. The median duration of the responseamong patients with antibody concentrations below 8.0 µgper milliliter was 71 days (95 percent confidence interval,57 to 88), as compared with 35 days (95 percent confidence interval,28 to 42) among those with antibody concentrations of 8.0 µgper milliliter or more (P<0.001) (Figure 4).
Figure 4. Duration of Response According to the Concentration of Antibodies against Infliximab before an Infusion.
Box plots show the median values and the first and third quartiles in each group. The T bars represent the rest of the data with a maximum of 1.5 times the interquartile range. The four categories can be divided in two groups: the first two categories have concentrations of antibodies against infliximab of less than 8.0 µg per milliliter and the last two have concentrations of 8.0 µg per milliliter or greater. The median duration of response in the first two groups differed significantly (P<0.001) from the median duration of response in the groups with titers of 8.0 µg per milliliter or higher.
Infliximab Concentrations
A significant relation was found (R2=0.34, P<0.001) betweenthe serum infliximab concentration at week 4 after an infusionand the concentration of antibodies against infliximab beforethat infusion. The overall median infliximab concentration fourweeks after an infusion was 12.0 µg per milliliter. Ascompared with patients who were not taking immunosuppressiveagents, patients who were taking immunosuppressive agents weremore likely to have infliximab concentrations of more than 12.0µg per milliliter (relative risk, 1.93; 95 percent confidenceinterval, 1.40 to 2.60). In a logistic-regression analysis ofvariables that were predictors of an infliximab concentrationof more than 12.0 µg per milliliter, including sex, typeof disease, fistula treatment regimen, the number of infusions,and the use of corticosteroids, mesalamine, or immunosuppressiveagents, only the use of immunosuppressive agents was significant(P<0.001).
Infliximab concentrations four weeks after an infusion weresignificantly lower among patients with a first infusion reactionthan among patients who had never had a reaction (1.2 µgper milliliter vs. 14.1 µg per milliliter, P<0.001).Once patients had had an infusion reaction they received prophylaxisconsisting of hydrocortisone and promethazine before subsequentinfusions. Among patients who had no further reactions whilereceiving prophylaxis, concentrations stayed high at four weeks(median, 12.9 µg per milliliter; 95 percent confidenceinterval, 1.9 to 21.0). Infliximab concentrations, however,were almost undetectable (1.0 µg per milliliter; 95 percentconfidence interval, 1.0 to 1.9; P=0.01) among patients whohad another reaction despite receiving prophylaxis (Figure 3B).Once an infusion reaction occurred, the median duration of responseto an infusion was shorter: 38.5 days (95 percent confidenceinterval, 34 to 51), as compared with 65 days (95 percent confidenceinterval, 56 to 71; P<0.001). This shortened response persistedduring further infusions irrespective of whether infusion reactionscould be prevented with prophylaxis (median, 42 days; 95 percentconfidence interval, 34 to 56) or not (median, 29 days; 95 percentconfidence interval, 24 to 106; P=0.17) (Figure 3C).
The infliximab concentrations at four weeks were positivelycorrelated with the duration of the response. Patients withinfliximab concentrations of 12.0 µg per milliliter orgreater had a median duration of response of 81.5 days (95 percentconfidence interval, 68 to 98), as compared with 68.5 days (95percent confidence interval, 52 to 77) among patients with infliximabconcentrations of less than 12.0 µg per milliliter (P<0.01).Logistic-regression analysis showed that the presence of antibodiesagainst infliximab was independently associated with a shorterduration of response (P<0.001 by the Kruskal–Wallistest), whereas the use of immunosuppressive agents (P=0.58)and the infliximab concentrations (P=0.70) were not.
Discussion
Infliximab has become common treatment for refractory Crohn'sdisease. Our data show that the development of antibodies againstinfliximab correlates with an increased risk of infusion reactionsand with a shorter duration of response owing to lower infliximabconcentrations. Our data suggest that treatment with immunosuppressiveagents prevents infusion reactions and helps maintain clinicalefficacy.
Several factors could account for the high incidence of antibodiesagainst infliximab in this cohort of patients. Since serialmeasurements were obtained in patients who were treated intermittently,the longer intervals between treatments afforded more opportunitiesto measure antibodies without the confounding presence of infliximabin the serum. All patients in the Anti-Tumor Necrosis FactorTrial in Rheumatoid Arthritis with Concomitant Therapy studyof rheumatoid arthritis11 and most patients in the ACCENT (ACrohn's Disease Clinical Trial Evaluating Infliximab in a NewLong-Term Treatment Regimen) study of Crohn's disease4 receivedinfliximab every eight weeks. Less than half the patients inour cohort were taking immunosuppressive agents, in contrastto the studies of rheumatoid arthritis, in which all patientswere taking methotrexate maintenance therapy.10 The assays inour studies were performed at Prometheus Laboratories and differedfrom the assay used by Centocor.4 A formal comparison of thetwo assays is warranted, but it is unlikely that differencesin methods will account for the differences in the incidenceof antibody positivity.
The results of measurements of antibodies against infliximabin serum samples obtained between infliximab infusions are oftenindeterminate. We therefore investigated whether measurementof the infliximab concentration four weeks after an infusionprovided more reliable results. Although there was a clear relationbetween infliximab concentrations and the duration of response,this correlation was not stronger than the correlation betweenthe antibody concentrations and the duration of response.
A clear message from our study is that immunosuppressive treatmentprevents the formation of antibodies against infliximab, thusreducing the incidence of infusion reactions and increasingthe duration of response. Infusion reactions are important immunologicevents induced by the presence of a substantial concentrationof antibodies against infliximab in the serum. After an infusionreaction, infliximab disappears quickly from serum and is undetectablefour weeks after an infusion. Once an infusion reaction occurred,the duration of the response to subsequent infusions decreased.Since antibodies develop soon after the initial infusion inmost patients, we think immunosuppressive therapy should beinstituted before infliximab therapy is started to prevent theformation of antibodies and improve the duration of responseto the drug.
Whether any one of the immunosuppressive agents — azathioprine,mercaptopurine, or methotrexate — provides greater protectionagainst immunogenicity remains to be determined. A drug interactionbetween methotrexate and infliximab has been proposed.12 Althoughthe maximal serum concentrations of infliximab are the samewith or without concomitant methotrexate therapy, the rate ofdisappearance of infliximab was slower in one study among patientswho were taking methotrexate than among those who were receivinginfliximab alone.12,13 To overcome the immunogenicity problem,humanized and human antibodies have been engineered and studiedin several diseases, including Crohn's disease.13,14,15,16,17,18Further studies will show whether these antibodies are associatedwith a reduced incidence of immunogenicity and an increasedratio of efficacy to safety.
Supported by a grant from the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen.
Presented in part at the American Gastroenterology AssociationDigestive Disease Week symposium in Atlanta, May 2001, and SanFrancisco, May 2002, and at the United European GastroenterologyWeek in Amsterdam, October 2001.
Drs. Van Assche, D' Haens, and Rutgeerts have reported servingas consultants to Centocor and Schering-Plough. Drs. D' Haensand Rutgeerts have reported serving as paid speakers for Centocorand Schering-Plough. Dr. Van Assche has reported serving asa paid speaker for Centocor. Dr. Rutgeerts has reported receivinggrant support from Centocor and Schering-Plough.
We are indebted to our data managers (Caroline Swijsen, KatrienAsnong, and Isolde Aerden) for the collection of data and serumsamples, to Eric Pauwels for invaluable help with the figures,and to Prometheus Laboratories (San Diego, Calif.) for the analysesof infliximab and antibodies against infliximab.
* Drs. Baert and Noman contributed equally to the article.
Source Information
From the Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg (F.B., M.N., S.V., G.V.A., G.D., P.R.); and the University Center for Statistics, Leuven University (A.C.) — both in Leuven, Belgium.
Address reprint requests to Dr. Rutgeerts at the Department of Internal Medicine, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium, or at paul.rutgeerts{at}uz.kuleuven.ac.be.
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is detected with horseradish peroxidase–conjugated antihuman IgG (Fc-specific). The cutoff value, which was based on the mean (+3 SD) value in serum samples from 40 patients who had never received infliximab, was 1.40 µg per milliliter. Concentrations below the cutoff value are reported as negative. In the case of 140 samples, concentrations greater than 20 µg per milliliter were reported as 21 µg per milliliter. 
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