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Combining infliximab with methotrexate for the induction andmaintenance of remission in refractory Crohn’s disease:a controlled pilot studyOliver Schro¨der, Irina Blumenstein and Ju¨rgen Stein Objectives Immunosuppression of chronic active Crohn’s (median time 2 versus 18 weeks) and needed fewer disease resistant or intolerant to purine antimetabolites steroids (median prednisolone dose 0 versus 11.8 mg).
still remains a clinical challenge. To obtain long-lasting Despite an increased mean number of adverse events effects with the anti-TNF-a antibody infliximab repeated per patient in the methotrexate group, the proportions infusions are often required. Methotrexate has been shown of patients experiencing any adverse events and to be a moderately effective drug in maintaining remission serious adverse events were similar across treatment in Crohn’s disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexateas therapy for refractory Crohn’s disease.
Conclusions The combination of infliximab with long-termmethotrexate may be a promising concept in refractory Methods Nineteen patients with chronic active Crohn’s Crohn’s disease. Our data prompt larger trials.
disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of inflix- imab (5 mg/kg) alone (n = 8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n = 11) European Journal of Gastroenterology & Hepatology 2006, 18:11–16 Keywords: azathioprine, Crohn’s disease, inflammatory bowel disease,infliximab, methotrexate, TNF-a, treatment Results Two out of eight patients receiving infliximabmonotherapy and four out of 11 patients treated with First Department of Internal Medicine, ZAFES, Johann Wolfgang Goethe infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of Correspondence to Oliver Schro¨der, 1st Department of Internal Medicine, efficacy. Clinical remission at week 48 was observed in five Division of Gastroenterology, Johann Wolfgang Goethe University, Theodor- out of seven patients treated with infliximab and metho- Stern-Kai 7, 60590 Frankfurt, Germany.
Tel: + 49 69 6301 6204; fax: + 49 69 6301 83112; trexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated withconcomitant methotrexate achieved remission earlier Received 27 June 2005 Accepted 20 September 2005 short-term response rates of up to 65% [3,4]. Three larger Without a definite cure for Crohn’s disease (CD), the trials have also recently focused on the long-term efficacy current standard therapy aims at suppressing intestinal of infliximab. Intervals of infliximab every 8 weeks inflammation. After the failure of first-line drugs, demonstrated prolonged benefit, although the response including sulfasalazine, 5-aminosalicylic acid, and corti- declines to some extent over time, which cannot be costeroids, immunomodulators such as azathioprine, 6- completely resolved by escalation of the infliximab dose mercaptopurine or methotrexate for long-term mainte- nance therapy are initiated. These drugs are used in orderto induce and maintain remission from CD flares, as well It is currently under discussion whether the concomitant as to reduce the requirement for longer-term corticoster- use of immunomodulator therapy provides clinical benefit oid use. During recent years the search for new drugs has in patients receiving repeated infliximab infusions mainly focused on biological agents that target specific [6,8,9]. In addition, no data are available evaluating the cytokines in the immune system. In 1994, the efficacy of use of infliximab as a short-term inducing agent in a chimeric IgG1 monoclonal antibody against TNF-a, infliximab, in the treatment of severe refractory rheuma-toid arthritis was reported [1]; soon afterwards, infliximab In this randomized, open-label, controlled pilot study we also proved its efficacy in severe refractory CD [2].
aimed to assess the efficacy and safety of a concomitant Meanwhile, two placebo-controlled, double-blind, rando- long-term immunosuppressive therapy with methotrexate mized trials in CD have been published showing overall to an induction scheme of infliximab in patients with Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
European Journal of Gastroenterology & Hepatology refractory CD resistant or intolerant to azathioprine. Our Patients receiving prednisolone had to maintain a stable hypothesis was that this therapeutic approach is superior dose for 4 weeks after the start of treatment, after which to the infliximab induction scheme alone. Secondary a defined tapering schedule was initiated in the case of an objectives included the assessment of the corticosteroid- improvement of the patient’s condition. Patients who had sparing effect as well as the safety of the combined entered the trial receiving prednisolone doses of more than 20 mg per day had their treatment tapered at amaximum rate of 5 mg per week; the maximum rate forpatients receiving 20 mg per day or less was 2.5 mg per Study patientsThe study design was a randomized, controlled, open- label, clinical trial carried out in accordance with the The primary endpoint of this study was clinical remission principles enunciated in the Declaration of Helsinki. The at the end of the trial as defined by a CDAI score of less study was approved by the local ethics committee of the than 150. Secondary analyses of efficacy included the Johann Wolfgang Goethe University in Frankfurt, Ger- time to achieve clinical remission and the corticosteroid- many. Recruitment of patients took place from Septem- ber 2001 until September 2003. Written informedconsent was obtained from all patients.
Evaluation of safetySafety was assessed in terms of the incidence of adverse Eligible patients had a history of chronic active CD, as events, changes in vital signs, and routine laboratory defined by refractoriness to or dependency on corticos- measures monitored during each infusion and at each teroids and resistance or intolerance to azathioprine.
Patients receiving the following treatment were eligible:5-aminosalicylates at doses of 4 g per day or greater, if the dose had been stable for 6 weeks before the screening Results are expressed as mean ± SD if not otherwise visit; corticosteroids (prednisolone) at a dose of 40 mg per indicated. Because the spread of results was not normally day or less (stable dose for 4 weeks before study entry).
distributed, non-parametric tests were used in the At entry into the study, none of the study patients had statistical analysis of data, namely the Mann–Whitney received previous treatment with infliximab or any other test for comparisons of non-paired series, and the Wilcoxon test for comparisons of paired series. Forqualitative data, the two-sided Fisher’s exact test wasapplied. Variations of P < 0.05 or less were considered to Patients were screened for eligibility one week beforeenrolment. The screening procedures included a com-plete physical examination, routine laboratory analyses, Statistical analysis was performed using the Jandel Sigma assessment of the severity of disease activity according to Stat 2.0 software package (RockWare Inc., Golden, the Crohn’s Disease Activity Index (CDAI) as well as a quality-of-life assessment by the Inflammatory BowelDisease Questionnaire (IBDQ), chest X-ray and liver function tests. At weeks 0 and 2, all patients received a Nineteen patients were screened, of whom all were 5 mg/kg body weight infusion of infliximab, which was randomly assigned. Of the randomly assigned 19 patients, administered intravenously in 250 ml saline solution over eight received infliximab monotherapy and 11 received 2 h. In addition, the patients randomly assigned at study the combination therapy. The baseline characteristics of entrance to be treated with concomitant methotrexate the two groups of patients were similar (Table 1).
also received six infusions of 20 mg methotrexate atweeks 0–5, followed by weekly oral methotrexate at a Two out of eight of the patients (25%) receiving dosage of 20 mg for 48 weeks. The dosage of methotrex- infliximab monotherapy (group I) but four out of 11 of ate was chosen according to the recommendations of the the patients (36%) treated with infliximab and concomi- tant methotrexate (group II) had discontinued studytreatment by week 48 (P = 1.00). The sole reason leading Patients were assessed at weeks 0, 2, 12, 24, and 48. At to the discontinuation of study treatment in both groups each visit, adverse events were prospectively collected by directly questioning the patients, and samples for clinicallaboratory assessments and the patient’s CDAI scores were obtained. In addition, health-related quality-of-life Throughout follow-up, patients assigned for continued remission treatment with methotrexate showed greater Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infliximab and methotrexate in refractory Crohn’s disease Schro¨der et al.
Baseline demographic data of the study patients CDAI, Crohn’s Disease Activity Index; GI, gastrointestinal; IBDQ, Inflammatory Bowel Disease Questionnaire; TI, terminal ileum.
Time course of Crohn’s Disease Activity Index in study patients treated Time course of Inflammatory Bowel Disease Questionnaire in study with short-term infliximab monotherapy alone or infliximab induction patients treated with short-term infliximab monotherapy alone or with therapy and long-term methotrexate (MTX). Clinical remission is defined infliximab induction therapy and long-term methotrexate (MTX).
as Crohn’s Disease Activity Index (CDAI) less than 150 as indicated by Quiescent disease is defined as Inflammatory Bowel Disease the dashed line. Data are presented as mean ± SD. —K— Infliximab plus Questionnaire (IBDQ) greater than 170 as indicated by the dashed line.
Data are presented as mean ± SD. —K— Infliximab plus methotrexate;—*— infliximab.
therapeutic benefit than patients receiving infliximab pattern of improvement between both groups favouring induction therapy alone. Overall, 10 out of 11 patients the combined treatment of infliximab with methotrexate (91%) treated with infliximab and methotrexate but only was seen for CDAI and IBDQ (Fig. 1 and Fig. 2).
four out of eight of the patients (50%) receivinginfliximab alone ever achieved clinical remission at one When looking at each visit during follow-up, however, no point during follow-up (P = 0.04). In addition, a clear significant differences between both groups could be trend was observed demonstrating that patients assigned observed. At week 2 seven out of 11 patients (64%) of for treatment with infliximab and concomitant metho- group II were in clinical remission whereas remission was trexate achieved earlier remission than patients receiving seen in only two out of eight patients of group I infliximab alone: the median time to achieve remission (P = 0.16). Treatment response increased in both groups was 2 weeks [interquartile range (IQR) 2–12] in group II until week 12, when nine out of 11 patients (82%) as compared with 18 weeks (IQR 7–48) in group I receiving concomitant methotrexate and four out of eight (P = 0.08). According to these findings, an analogous patients (50%) treated with infliximab monotherapy were Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
European Journal of Gastroenterology & Hepatology in remission (P = 0.32). Thereafter, therapeutic response observed during follow-up (Table 2). The proportions of decreased in both groups over time: remission at weeks patients experiencing any adverse events and serious 24 and 48 was observed in six out of 11 (55%) and five adverse events were similar in the two treatment groups.
out of 11 (45%) patients treated with infliximab and No patient had to withdraw from the study because of methotrexate, respectively. For infliximab monotherapy, drug-related adverse events. There was a clear, yet not remission at weeks 24 and 48 was found in three out of significant, trend towards more frequent adverse events in eight (38%) and two out of eight (25%) patients, the methotrexate group known to be associated with this respectively (P = 0.65 and P = 0.63).
drug (abnormal liver function tests, fatigue, headache). Anadjustment of the methotrexate dosage regimen in the At week 48, all seven patients in group II completing the seven patients with elevated liver enzymes was not trial but only two out of six patients (33%) in group I necessary because increased transaminase concentrations finishing the study had discontinued corticosteroids (up to three times the normal range) were transient in all (P = 0.02). The mean prednisolone doses over time up cases. In addition, no severe infections were observed in either group during follow-up and no malignant disorderoccurred during the course of the study.
SafetyA trend towards an increased mean number of adverse events per patient in the methotrexate group could be The natural history of CD is characterized by chronicactivity in approximately half of the patients [10,11]. Inthe past two decades, the use of immunosuppressive agents has been established as the therapy of choicein the management of chronic active CD. Within this treatment algorithm, azathioprine and its metabolite 6-mercaptopurine are well accepted as first-line drugs.
Despite their established efficacy, a rather large propor-tion of patients will not respond to or will have todiscontinue medication because of intolerable side- effects [12,13]. In addition, the low onset of action mayhamper the use of thiopurines in situations of pro- nounced severity of the disease. In Germany, methotrex- ate is used as a second-line immunosuppressive agent inthe case of inefficacy or intolerance to azathioprine/6- mercaptopurine [14]. This drug has been shown to be amoderately effective and safe treatment in chronic active glucocorticoid-dependent CD [15]. However, methotrex- ate also lacks a rapid onset of action.
Mean daily prednisolone dose in study patients treated with short-term Among the newer biological agents being developed in infliximab monotherapy alone or with infliximab induction therapy andlong-term methotrexate (MTX). Data are presented as mean ± SD.
recent years, the addition of infliximab to the armamen- —K— Infliximab plus methotrexate; —*— infliximab.
tarium of remedies to fight CD has significantly changedthe medical management of this disease, both in the Adverse events in the two treatment groups No. of patients with serious adverse events Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infliximab and methotrexate in refractory Crohn’s disease Schro¨der et al.
short-term induction of remission and in maintenance.
immunosuppressive therapy based on a short-term The rates of clinical remission at week 4 in patients with remission induction by infliximab accompanied by long- inflammatory disease unresponsive to conventional ther- term maintenance methotrexate in patients with chronic apy after a single infusion were 48% for infliximab 5 mg/kg active CD resistant or intolerant to azathioprine.
compared with 4% for placebo [3]. Rates for one year’s Combination treatment was compared with an induction maintenance of clinical remission in patients who had therapy with infliximab at a concentration of 5 mg/kg responded to induction treatment with infliximab were body weight administered twice in a fortnightly interval.
up to 24–32% for infliximab every 8 weeks (depending onthe administered dose) but only 9% for placebo [6].
There is still much debate about the optimal regimen of Nevertheless, it must be stressed that only 58% of infliximab in the treatment of CD [3,4,6,7]. In the initial patients had demonstrated responsiveness to the drug.
induction of remission study for patients with activeinflammatory CD, a single infliximab infusion was As a result of the high cost of repeated infusions and the administered [2]. In contrast, in patients with fistulizing lack of efficacy in a large proportion of treated patients CD as well as in the ACCENT I trial, a three-dose there is a need for the identification of demographic and induction sequence has been used, with doses adminis- clinical characteristics that could predict response to the tered at 0, 2, and 6 weeks. Another large trial in patients drug. Among the clinical variables, concomitant immu- with active inflammatory CD compared one-dose versus nosuppressive medication has been discussed as an three-dose induction strategies, and found better short- independent variable, although no significant benefit term clinical response rates for patients who received has yet been demonstrated. In the ACCENT I trial, 50% three-dose induction compared with one-dose induction of patients who received a concomitant baseline im- therapy [24]. Whether the improved clinical response munosuppressive medication with azathioprine/6-mer- truly represents a short-term advantage for the three-dose regimen has not been formally tested in a randomized response throughout the study compared with 41% of controlled trial. However, there is expanding evidence those not receiving these drugs [6]. Comparably, a similar that patients who receive some infusions for induction response between patients receiving immunomodulators therapy may develop an immunological ‘tolerance’ to (86.4%) and patients receiving infliximab alone (75%) infliximab, as indicated by the reduced rate of infusion was also observed in a retrospective study in 117 patients reactions and delayed hypersensitivity reactions [25,26].
treated with ‘on demand’ infliximab [8]. Despite these The non-standard induction regimen applied in our pilot rather disappointing data, there is also good theoretical study therefore represents a compromise with respect to and clinical evidence advocating the combined use of the existing induction regimens for infliximab.
infliximab and immunomodulatory drugs. Several largerandomized, controlled trials in patients with rheumatoid As expected, the results of this trial indicate that long- arthritis revealed the greater benefit of a combination term maintenance therapy with low-dose methotrexate, therapy with methotrexate and infliximab than infliximab after an induction treatment with infliximab, provides alone [16–19]. In addition, two recently published pilot important benefits compared with an induction therapy studies by us and others [20,21] demonstrated that by infliximab alone. The beneficial outcome of the concomitant long-term thiopurine or methotrexate ther- combination therapy does not seem to be restricted to apy can prolong the effect of a three-dose treatment long-term clinical response, but also extends to the time course of infliximab in patients with fistulizing CD. The interval until remission is achieved. The reason for this observed additive or synergistic efficacy of a combination phenomenon is unclear, but may be related to the therapy described in such studies may be based on both different modes of action of the two immunosuppressive the different modes of action but also on the lower agents or probable drug interactions between infliximab formation of human antichimeric antibodies, also known and methotrexate, as proposed by Maini et al. [25]. Such as antibodies to infliximab. These antibodies occur in 30– interactions have already been described for infliximab 75% [9,22,23] treated episodically with infliximab with- and azathioprine in CD patients [27]. In accordance with out a concomitant immunosuppressive agent and are the improved response, the proportion of patients who believed to reduce the therapeutic benefit and the were able to reduce or even to stop corticosteroids was incidence of infusion reactions to infliximab [22,23]. In larger in the group receiving infliximab with concomitant contrast, the co-administration of immunosuppressive methotrexate than in the infliximab monotherapy group.
therapy resulted in a decreased incidence of human This steroid-sparing effect of such a therapeutic regimen antichimeric antibody (antibodies to infliximab) forma- depicts another treatment advance in the management of This randomized, controlled pilot study evaluated for the Maintenance low-dose methotrexate after infliximab first time the efficacy and safety of a combination induction therapy was generally well tolerated. Although Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
European Journal of Gastroenterology & Hepatology the number of adverse events was larger in patients Baert F, Noman M, Vermeire S, Van Assche G, D’Haens G, Carbonez A, receiving the combination therapy compared with the Rutgeerts P. Influence of immunogenicity on the long-term efficacy ofinfliximab in Crohn’s disease. N Engl J Med 2003; 348:601–608.
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