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Journal of Crohn's and Colitis: 10 (9)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium

6.585
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Published on behalf of

Is the efficacy of successful infliximab induction therapy maintained for one year lasting without retreatment in different behavior types of Crohn's disease?

T. Molnár, K. Farkas, P. Miheller, T. Nyári, Z. Szepes, L. Herszényi, Gy Müzes, F. Nagy, Zs. Tulassay, T. Wittmann
DOI: http://dx.doi.org/10.1016/j.crohns.2008.07.003 322-326 First published online: 1 December 2008

Abstract

The high cost of infliximab inhibits the regular retreatment of all patients in Hungary with Crohn's disease (CD) after beneficial induction therapy. This study is set out to evaluate the medium-term efficacy of induction therapy with infliximab without retreatment in CD patients with chronic activity and/or fistulae refractory to conventional therapy.

Methods: A retrospective 1-year review was undertaken of all CD patients with successfully induced remission or fistula closure with 3 infusions of infliximab. Infliximab was administered in a dose of 5 mg/kg 3 times, in weeks 0, 2 and 6. Clinical remission was defined as symptom resolution and an estimated Crohn's Disease Activity Index (CDAI) < 150 and complete fistula closure. We evaluated the clinical response, the estimated CDAI, the number of draining fistulae, the dosages of steroid and immunosuppressive drugs at 6 and 12 months after the last infusion, and the needs for hospitalization and surgical intervention during this period. Breslow (Generalized Wilcoxon) test was used as the statistical method.

Results: The data of the 50 patients (19 luminal, 31 fistulizing disease; average age 29. 3 [13–59] years, disease localization: 23 colon, 13 ileum, 13 ileocolon, 1 duodenum) were suitable for analysis. Infliximab induction therapy without retreatment resulted in a beneficial effect lasting for at least 1 year in 22 of the 50 patients (44%). 11 of the 19 patients (57.9%) with luminal disease remained in steroid-free complete remission, while the fistulae persisted closed in only 11 of the 31 patients (35.5%) (p < 0.05).

Conclusion: Infliximab induction therapy alone may result in sustained remission mainly in patients with luminal disease. These results suggest the need for maintenance therapy with infliximab after successful therapy induction in patients with fistulae, while luminal CD patients could possibly participate in regular retreatment only if needed. If these data are confirmed, this modification of the therapeutic procedure could well increase the cost-effectiveness of infliximab.

Keywords
  • Crohn's disease
  • Infliximab induction therapy
  • On demand treatment

1 Introduction

The majority of patients with Crohn's disease (CD) do not have a good quality of life and are unable to continue their everyday life due to frequent relapses and severe extraintestinal, intraabdominal or perianal complications in spite of conventional maintenance treatment. Anti-TNFα blocking agents can be effective and safe therapeutic options in this large group of patients refractory or intolerant to conventional therapy. In Hungary, Infliximab (Remicade, Schering Plough), the first, widely used standard biological agent was registered in 2001 for the treatment of both luminal and fistulizing CD patients not responding to corticosteroids and immunosuppressive treatment or showing intolerance or hypersensitivity to such therapies. Therefore, Hungarian regulations do not allow the early use of infliximab with immunosuppressants as a top-down therapy, although this form of therapy has been proven to be advantageous in the mucosal healing, in the suppression of inflammation and – statistically only in the first year – in maintaining remission (1). In Hungary (and we think also in many other countries) the main limitation in the use of infliximab is its cost (the cost of two treatments with 3-3 ampoules is the same as the cost of monthly drug quota of an 80-bed clinic). Therefore, although controlled trials in refractory patients have shown better clinical and endoscopic results for scheduled treatment every 8 weeks, maintenance treatment after a successful induction is feasible only in a minority of all cases in Hungary (in the last 5 years 13% of the patients have been given maintenance treatment in the departments involved in our study) — mainly due to financial reasons. However, we know studies and life are different, in the above-cited very important publication of a 2-year open label randomized trial at 18 centres in Belgium, Holland, and Germany between 2001 and 2004, also episodically infliximab retreatment was used in the top-down group according to their daily practice.1

Our study evaluates retrospectively the efficacy of infliximab induction therapy without scheduled retreatment in different subgroups of CD, and aims to assess whether induction therapy is worth to start when maintaining a successful treatment for at least one year has limited feasibility. We would like to accurately determine which group of patients could have long-lasting benefit just from the induction therapy and which factors might have a prognostic value.

2 Patients and methods

50 CD patients, who had reached successful remission (luminal group) or complete fistula closure (fistulizing group) after infliximab induction therapy, and who had been diagnosed for at least 24 months based on the appropriate criteria, were enrolled in the study.2 Indication of infliximab induction therapy was active luminal disease due to steroid dependency and/or therapy-resistant CD in 19 and presence of draining fistula in 31 patients.

According to the application and clinical practice guidelines infliximab was administered in a dose of 5 mg/kg 3 times, in weeks 0, 2 and 6 for all patients in both groups during induction therapy. Induction therapy, patient controls and data analysis were performed in two tertiary university centers.

Data were analyzed retrospectively; our therapeutic decisions were based only on the clinical activity of the disease and on our actual facilities, the study itself did not have any influence on them. Table 1 contains separately the data of luminal and fistulizing CD patients participating in the study.

View this table:
Table 1

Data of patients at the beginning of infliximab induction therapy

Number of patient with luminal CD (n = 19)Number of patient with fistulizing CD (n = 31)
Sex
Female1115
Male816
Average age of the patients at the beginning of the disease (year)28.5 (16–59)29.8 (13–59)
Present age of the patients (year)39 (19–86)38.5 (20–86)
Average duration of the disease (year)10 (2–31)8.7 (3–27)
Localization
Colonic914
Ileal310
Ileocolonic67
Duodenal10
Medical treatment before induction therapy
Corticosteroid treatment117
Immunosuppressive treatment1627
Smoker patients at the time of induction therapy811
Positive family history of IBD25

The average age of the patients was 29.3 years (min. 13, max. 59). 26 females and 24 males participated in the study. Groups formed by disease localizations included 23 colonic, 13 ileal, 13 ileocolonic and 1 duodenal. 18 patients received corticosteroids (methyl-prednisolone, average dose: 9 mg/day; 4–32 mg/day), 43 (86%) immunosuppressants and 16 of them needed combined corticosteroid and immunosuppressive treatment at the time of the induction therapy. Azathioprine was administered to 39 (average dose: 125 mg/day, 25–200 mg/day), 6-mercaptopurine (average dose: 75 mg/day; 50–100 mg/day) to 3 and methotrexate (dose: 25 mg/week) to 1 patient. In all cases at least one year elapsed between the beginning of the immunosuppressive treatment and the infliximab induction therapy.

After the successful induction therapy patients were examined at least once in every three months. We altered the dose of the applied drugs in accordance with the actual condition of the patients. Data of month 6 and 12 controls were selected for statistical analysis. Clinical symptoms, the estimated Crohn's Disease Activity Index (CDAI), the number of draining fistulae, changes in the dosages of steroid and immunosuppressive drugs, the need for repeated (on demand) infliximab infusion due to exacerbation were evaluated. We also assessed the need for hospital admissions and the number of surgical interventions related to CD during the 12 months after the induction therapy. Clinical remission was defined as an estimated Crohn's Disease Activity Index (CDAI) < 150 at both controls of months 6 and 12 in the luminal group, the absence of draining fistula, if the dose of the immunosuppressants was steady and the dose of corticosteroids could be tapered. Relapse was defined as a flare up (CDAI > 150) or as a recurrence of draining fistulas within a year after successful induction therapy; if the dose of corticosteroid and immunosuppressive drugs had to be increased or surgical intervention was needed due to the development of fistula, perianal abscess or stenosis; and if readministration of infliximab was required. Breslow (Generalized Wilcoxon) test was used for statistical analysis and p values < 0.05 were considered statistically significant.

3 Results

3.1 At 6th month

Beneficial effect achieved by infliximab induction therapy remained in 28 of the 50 (56%) patients in the first 6 months. 15 of the 19 (78.9%) patients with luminal CD did not have relapse during this period. In all these 15 cases there was no change in the immunosuppressive drug dose, while corticosteroid treatment could be discontinued in 12 patients. Out of the 4 patients in whom exacerbation developed, 2 required infliximab retreatment, 2 needed parenteral steroid therapy and increase in the dose of immunosuppressants during hospital admission in all cases. In the first 6 months drainage from fistulae ceased in 13 of the 31 (41.9%) patients suffering from fistulizing Crohn's disease besides unchanged type and dose of immunosuppressive treatment (Fig. 1). Surgical treatment of complicated fistula was performed in 3 cases, on demand infliximab treatment was required in 8 patients and an increase in the dose of the immunosuppressive drugs was indicated in 7 cases.

Figure 1

Proportion of the patients in remission at the end of month 6 and 12.

3.2 At 12th month

22 (44%) patients remained in complete steroid-free remission at the end of month 12. 11 (57.9%) of the 19 patients with luminal and also 11 (35.5%) of the 31 cases with fistulizing disease did not show clinical activity or fistula draining at the end of the first year (there is a significant difference between the two groups, p = 0.014) (Fig. 2). Hospital admission was indicated in further 7 cases of all of the patients (4 because of disease activity, 3 due to fistulae treatment).

Figure 2

Kaplan–Meier survival curve for patients remaining in remission in luminal and fistulizing group.

Analyzing the patients being in remission at month 6 (15 luminal, 13 fistulizing types) 4 patients in the luminal group had flare up in the second term of the study, and parenteral steroid therapy was applied in all cases. 2 of the 13 patients with active, complicated fistulizing disease needed surgical intervention. Infliximab induction therapy was not repeated in the second term of the investigation.

8 of the patients with colonic, 7 with ileal, 6 with ileocolonic, and 1 with duodenal localization remained in remission at the end of the year (Fig. 3).

Figure 3

Proportion of the patients in remission at the beginning of the study and at month 12 in consideration of the disease localization.

6 of the 19 smoker patients (31.6%) remained in remission at the end of the month 12, vs.16 of the 31 non-smoker (51.6%) patients (Fig. 4). Statistical significance was not detected in groups made by localization and smoking between patients having active disease and being in remission.

Figure 4

Proportion of the patients in remission in the consideration of smoking.

4 Discussion

Infliximab is an accepted treatment for inducing and maintaining remission in active luminal and fistulizing Crohn's disease not responding to conventional corticosteroid or immunosuppressive therapy or developing intolerance or hypersensitivity to them.3 Beneficial induction therapy is recommended to be followed by maintenance infliximab infusions every 8 weeks thereafter. However, in clinical practice on demand treatment is often required due to the lack of patient cooperation (missed controls) or financial causes. In such cases patients who relapse receive repeated infliximab induction therapy apart from the elapsed time. ACCENT I and II, which are ones of the largest clinical trials dealing with the therapeutic results of Crohn's disease, confirmed the beneficial effect of the regular maintenance infliximab therapy both in luminal and fistulizing Crohn's disease. 58% of 573 patients with luminal Crohn's disease participating in ACCENT I study responded to infliximab induction therapy (only one infusion!). 28 and 38% of them receiving maintenance infliximab therapy 5 and 10 mg/kg every 8 weeks remained in remission at week 54. Corticosteroid treatment was used in 67%, immunosuppressants in 29% of the patients at the beginning of ACCENT I study. Corticosteroid could completely be discontinued in 25% of the patients during the treatment. In addition, a significant decrease was seen in the need for hospitalization and the number of surgical interventions. These study findings suggested that significantly greater proportion of the patients were in remission in case of regular maintenance treatment with infliximab compared to episodic therapy.4 In the ACCENT II trial 36% of 195 patients, who responded to the infliximab induction therapy of the total 306 patients with fistulizing Crohn's disease, remained in remission with the absence of draining fistula at week 54.5

However, an earlier observation by Domenech et al.6 revealed a surprisingly good 6-month result after successful three-infusion based induction therapy without retreatment in patients with luminal CD, only 5 of the 18 patients relapsed during that time.

Since our facilities were not enough to ensure regular 8 weekly maintenance treatment with infliximab for all patients responding to the induction therapy, we retrospectively analyzed which useful conclusions can be made in case of this application form and in which subgroups of patients with Crohn's disease is episodic infliximab therapy recommended. Data of those patients were retrospectively analyzed, who were not treated with infliximab regularly after a successful induction with anti TNFα. We were interested in which subgroups of patients is infliximab induction therapy worth to be used if maintenance treatment would not probably be available. One year, “medium-term” efficacy was assessed during our study.

22 of 50 patients remained in remission for at least one year without retreatment after successful infliximab induction therapy. Significant majority of the patients being in permanent remission was classified in the luminal patient group. 57.9% of the patients with luminal Crohn's disease were in remission at the end of the year compared to the remission rate of 35.5% in case of fistulizing patients (p = 0.014). Corticosteroid treatment using at the beginning of the infliximab induction therapy could completely be discontinued in patients remaining in remission at the end of month 12.

According to some literature data active inflammation with high CRP level, isolated colon localization of Crohn's disease, absence of intestinal stenosis, co-administration of immunosuppressive drugs and newly diagnosed childhood CD suggest beneficial influence on the outcome of infliximab treatment, while smoking impairs the therapeutic results.7,8

Contrary to these data, results of Domenech et al. and our findings did not confirm that remission continuity was influenced by the disease location, while among smoker patients – consistent with the literature data – therapeutic failure was more frequent (51.6 vs. 31%), although statistical significance could not be verified. Our results support that regular retreatment with infliximab helps to achieve permanent therapeutic effect after successful induction therapy in patients with fistulas. In luminal CD patients, especially in non-smokers, retreatment can be used only if needed. Comparing the data of ACCENT I trial and ours, we observed high remission rate at one year among patients with luminal Crohn's disease without maintenance biological treatment. This can be explained by the use of immunosuppressive therapy in most of the patients (86% of our patients received immunosuppressive drugs vs. 29% of the patients in ACCENT I study) and by the fact that only those patients were enrolled in the study who achieved remission or whose fistulas completely closed at the end of induction therapy. Our results represent the medium-term efficacy of infliximab induction therapy in luminal cases, non-smokers, apart from the disease localization and with continuous use of immunosuppressants. Results of patients with fistulizing Crohn's disease suggest that infliximab induction therapy might not be worth using in the absence of the possibility of a regular retreatment with infliximab.

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View Abstract