Correspondence to: Dr M. G. V. M. Russel, PO Box 5800, NL-6202 AZ Maastricht, The Netherlands. E-mail: firstname.lastname@example.org
Background : Infusion of anti-tumour necrosis factor-α appears to be highly effective in patients with Crohn's disease.
Aim : To assess the effect of infliximab on the quality of life in patients with active or fistulizing disease, as measured by the inflammatory bowel disease questionnaire, and to examine the impact on its four dimensions.
Methods : An observational study was conducted in 65 patients. An infusion of 5 mg/kg infliximab was given at week 0 in patients with active disease and at week 0, 2 and 6 in fistulizing disease. Changes from baseline in the total and dimensional inflammatory bowel disease questionnaire scores were calculated and compared between the patient groups. Potential predictors of change in the quality of life were identified.
Results : In the active disease group, at week 4, the mean total and dimensional inflammatory bowel disease questionnaire scores improved compared to baseline (P < 0.001). In the fistulizing group, at week 6, all scores changed from baseline (P < 0.05). Improvement in the total inflammatory bowel disease questionnaire score correlated well with the improvement of the Crohn's disease activity index. Systemic and social scores improved more than bowel and emotional scores. Inflammatory Crohn's disease and a young age at diagnosis were predictors for a better response to infliximab therapy.
Conclusions : Infliximab therapy improves all dimensions of the quality of life in patients with Crohn's disease.
Health-related quality of life is a valuable parameter in patients with inflammatory bowel disease.1–3 The inflammatory bowel disease questionnaire (IBDQ) has been reported to be a specific and useful tool for its assessment.4–6 The IBDQ can be subdivided into four dimensions: disease activity (e.g. stool frequency and abdominal pain or cramps), systemic complaints (e.g. fatigue and energy loss), emotional functioning (e.g. depressed feelings) and social well-being (e.g. limited sexual activity).
Standard therapy for Crohn's disease is effective in most patients, but a small group remains refractory. Infliximab (an anti-tumour necrosis factor-α, anti-TNF-α) has been increasingly used in such cases. To date, several studies have shown that infliximab is efficacious in the treatment of fistulizing and active Crohn's disease.7–20 Disease activity, as measured by the Crohn's disease activity index (CDAI), decreased in the majority of patients and fistula closure was obtained in half of the patients studied. Changes in the quality of life, as measured by the IBDQ, were assessed in some of these trials, but none reported specifically the effect of infliximab on the IBDQ dimensions, or studied the predictors of change in the quality of life.
The aim of this study was to examine the effect of infliximab on the quality of life, as measured by the IBDQ, and on the four dimensions of this questionnaire in patients with moderately to severely active Crohn's disease or with fistulizing disease refractory to standard therapy. Furthermore, potential predictors of change in the quality of life in these patients were investigated.
Patients participating in the multicentre trial, ‘Expanded Access Program for Anti-TNF Chimeric Monoclonal Antibody (infliximab)’, in five university hospitals in The Netherlands (Amsterdam, 19 patients; Leiden, 26 patients; Utrecht, seven patients; Groningen, five patients; Maastricht, eight patients) were eligible for the present study. Moderately to severely active Crohn's disease was defined by a CDAI of ≥ 200 (possible range, 0–700). Patients were excluded if they had received prior treatment with infliximab, had severe infection, symptomatic stenosis or ileal strictures. Patients with more than one missing question per IBDQ dimension were also excluded from this study.
Data from 65 patients who participated in the trial were available. Of these, nine patients were withdrawn. The reasons for doing so were an inability to complete the IBDQ because of a language problem (n = 1), incomplete follow-up (n = 3) and many missing questions from the bowel dimension because of a stoma (n = 5).
All patients received an infusion of 5 mg/kg body weight infliximab at entry and patients with fistulae also received an infusion at weeks 2 and 6. The CDAI and IBDQ were assessed at screening, 4 and 8 weeks after infusion in patients with active Crohn's disease, and 2, 6 and 10 weeks after the first infusion in patients with fistulae. The study was approved by the local medical ethical committees and all patients gave written informed consent before the start of the study.
The inflammatory bowel disease questionnaire
The IBDQ is a disease-specific, health-related quality of life questionnaire. It contains 32 items, with a graded response range of 1 (worst) to 7 (best), and a total score range of 32–224. In a Canadian study, healthy people had an average score of 213 (6/7 per question).21 The 32 items can be divided into four dimensional scores, including bowel symptoms (10 items), systemic symptoms (five items), emotional well-being (12 items) and social function (five items).1 The IBDQ has been translated and validated into the Dutch language and proved to be valid, discriminative and reliable.22
The IBDQ was assessed at each visit, when the total score was calculated, as well as the four individual dimensional scores. The aim of this study was to measure the change in total and dimensional scores of the IBDQ from baseline. In addition to the IBDQ, the CDAI was measured, to assess the disease activity and calculate the correlation between the CDAI and IBDQ, including its four dimensions. Data on age, sex, age at diagnosis, duration of disease and type of Crohn's disease were collected from medical records.
The Kruskal–Wallis test was used to compare the IBDQ and CDAI scores between the five centres. The mean scores of the IBDQ and the four dimensional scores were compared between baseline and each visit using paired sample t-tests. The percentage change of the IBDQ was compared between the two treatment groups using an independent sample t-test. Improvements in each of the four dimensional scores were compared using paired sample t-tests and the Friedman test. The Pearson correlation coefficient was used to examine the correlation between the CDAI and the IBDQ at baseline and the change between weeks 0 and 4 (active disease) and between weeks 0 and 10 (fistulizing disease). Linear regression analysis was used to examine potential predictors of change of the IBDQ and its four dimensions from baseline. For the evaluation of the IBDQ forms, one missing question per dimension was allowed, and corrected by calculating the IBDQ score with the average dimensional score, assuming that there was one missing question per dimension. Because some patients failed to fill in all the IBDQ forms, we used the technique of ‘last observation carried forward’.
Two-tailed tests for significance were used in statistical analyses. A P value of < 0.05 was considered to be statistically significant. The Statistical Package for the Social Sciences (SPSS 10.0, SPSS Inc., Chicago, IL, USA) was used for all analyses.
The demographic features of the patients are shown in Table 1. They are divided into two groups: patients with active Crohn's disease and patients with fistulizing disease. Patients with active Crohn's disease had significantly higher mean CDAI scores (P < 0.01) and lower IBDQ scores (P < 0.001) at entry than patients with fistulae. CDAI and IBDQ scores at baseline were not different between the five centres.
Table 1. Demographic features of 19 patients with active Crohn's disease and 25 patients with fistulizing Crohn's disease at baseline
The IBDQ in the active Crohn's disease group improved significantly 4 weeks after the single infusion from 117.5 ± 17.7 to 168.7 ± 31.8 (P < 0.0001, increase of 51.2; 95% confidence interval (CI), 36.7–65.7). All four dimensional scores also increased (P < 0.001). Eight weeks after infusion, the IBDQ scores had a slightly decreasing trend compared to week 4 (Figure 1).
In the fistulizing group, the total IBDQ score improved 2 weeks after infusion from 151.8 ± 33.9 to 164.0 ± 29.2 (P = 0.002, increase of 12.2; 95% CI, 4.8–19.7). Improvement was also significant in the systemic, emotional and social dimensions (P < 0.05), but not in the bowel dimension. All dimensional IBDQ scores improved from baseline at 6 weeks, after two infusions (P < 0.05), and at 10 weeks, after three infusions (P < 0.01) (Figure 2).
The total IBDQ score in patients with active Crohn's disease was maximal at 4 weeks, after one infusion (168.7 ± 31.8), whereas, in patients with fistulae, the score was maximal at 10 weeks, after three infusions (179.6 ± 25.5) (Figure 3).
The percentage of improvement was higher in the active disease group than in the fistulizing group for the total IBDQ (46% vs. 25%, respectively; P < 0.05), the bowel dimension (43% vs. 19%, respectively; P < 0.05) and the systemic dimension (84% vs. 33%, respectively; P < 0.01).
The total IBDQ and CDAI scores at baseline correlated significantly (R = − 0.54, P < 0.001) and, in addition, all dimensions separately correlated well. In patients with active Crohn's disease, the percentage change in CDAI and IBDQ scores between weeks 0 and 4 correlated with regard to the total score (R = 0.732, P = 0.001) and all the dimensional scores separately. In patients with fistulizing disease, the percentage change in CDAI and IBDQ scores between weeks 0 and 10 only correlated for the systemic dimension (R = 0.353, P < 0.05) (Figure 3).
Significant differences were found between dimensional changes in patients with active Crohn's disease between weeks 0 and 4. The improvement in the systemic (83.7%; P = 0.005) and social (99.9%; P = 0.018) dimensions was higher than the improvement in the bowel (42.7%) and emotional (37.3%) dimensions. In patients with fistulae, the systemic dimension (33.0%) improved more than the bowel dimension (19.2%; P = 0.018), and the social dimension (48.5%) improved more than the bowel and emotional dimension (24.0%; P < 0.05), between weeks 0 and 10. These results were confirmed by the Friedman test (P < 0.05).
To identify predictive variables of improvement in the IBDQ score, the variables age, sex, duration of disease, age at diagnosis, fistulizing or active disease and the CDAI at onset were put into a linear regression model. An early age of onset of disease (P < 0.05) and active disease (P < 0.01) proved to be significant predictors of improvement in the total IBDQ score and three dimensional scores: bowel, systemic and emotional. A higher CDAI at onset was a significant predictor of improvement in the social score (P = 0.04).
The results of this study show that infliximab rapidly improves the quality of life in patients with active and fistulizing Crohn's disease, as measured by the IBDQ. In patients with active disease, the improvement in all IBDQ dimensions was seen at the first screening visit 4 weeks after the single infusion of infliximab. Systemic and social scores improved more than bowel and emotional scores. The maximum dimensional scores were also reached 4 weeks after the single infusion. The improvement in the CDAI correlated well with the improvement in all dimensional scores in this group.
In patients with fistulizing disease, all dimensions improved significantly 6 weeks after the first infusion, but systemic, emotional and social scores improved 2 weeks after the first infusion. The quality of life was maximal after 10 weeks, 4 weeks after the third infusion. Because this was the last screening visit, a further improvement in the quality of life could potentially have occurred. The CDAI increase correlated well with the change in the systemic score.
Both inflammatory Crohn's disease and an early age of onset of disease were strong predictors of a higher efficacy of therapy with regard to improvement in three out of four of the dimensional scores. For the social dimension, on the other hand, a higher disease activity was predictive of greater improvement.
Several studies have described the improvement in the quality of life after infusion with infliximab, but the effect in fistulizing or active disease was not evaluated separately in these studies.7,9,10,12 In a multicentre trial comparing three doses of infliximab with placebo in patients with moderately to severely active Crohn's disease, the total IBDQ score in the 5 mg/kg group improved significantly after 4 weeks in 81% of patients compared to placebo.10 After 8 and 12 weeks, the score slightly, but not significantly, decreased, comparable to the results in the present study. This effect was noticed in both the total and dimensional IBDQ scores.
In a study by Present et al., the effect of infliximab on fistula closing was investigated, but no data on the quality of life were collected.8 The effect was seen 2 weeks after the first infusion of infliximab and the median duration of response was 3 months. In 55% of patients treated with 5 mg/kg infliximab, all fistulae closed, compared to 13% with placebo. In our study, no data on fistula closing were collected. The time to improvement in the quality of life in the current study is comparable with the time to fistula closure observed by Present et al. Some patients in the fistulizing group only had fistulae as a complication and other patients had both active disease and fistulae. Because these two types of patients were combined in the same group, and fistula closing was not measured, it was not clear whether fistula closure or decreased inflammatory activity was responsible for the improvement in the quality of life in this patient group.
Cytokines such as TNF-α can influence human behaviour during inflammatory conditions.23–25 Changes in this behaviour include decreased sexual drive (social dimension) and increased sleep, decreased appetite and fatigue (systemic dimension). Infliximab decreases the amount of circulating TNF-α, which is increased in Crohn's disease, and as a result it might influence the behavioural symptoms in Crohn's disease. The role of cytokines in regulating mood (emotional dimension) still remains speculative.24 This could possibly explain why the systemic and social dimensions improve significantly more than the emotional and bowel dimensions.
Despite our relatively small sample size, the IBDQ proved to be a valid measurement of health status in patients with Crohn's disease, and correlated well with the improvement in disease activity as measured by the CDAI. The correlation between the bowel dimension and the CDAI was more prominent, probably because the CDAI contains items related to the bowel dimension. Although the presence of fistulae is calculated in the CDAI, the CDAI is not a very useful tool to measure disease activity in patients with fistulizing disease.26,27 The perianal disease activity index (PDAI) could be a more useful tool, but was not assessed in this study.
Predictors of the clinical course of Crohn's disease have been investigated in several trials. The age at onset of diagnosis as a predictive value has been described previously. Polito et al. retrospectively reviewed 552 consecutive patients with Crohn's disease, and specifically investigated the influence of age at diagnosis.28 It was found that patients diagnosed at an early age were more likely to have a positive family history of Crohn's disease, more frequent ileal disease and a greater need for surgery. This corresponds to a worse course of the disease in this patient group. They assumed that Crohn's disease patients with a young age at diagnosis had a different genetic component and thereby a different phenotypic expression. Our findings that a young age at diagnosis is a predictor for higher efficacy of infliximab treatment could support this theory of different disease expression between early and later onset of Crohn's disease.
From this study, we conclude that infliximab at a dose of 5 mg/kg improves the quality of life in patients with both active and fistulizing Crohn's disease. A young age at diagnosis and active disease predict a better response of the quality of life to this therapy. We hypothesize that a reduction in circulating cytokines in active and fistulizing Crohn's disease influences well-being, as demonstrated by the improvement in the systemic and social dimensions after treatment with infliximab.
All patients participated in the ‘Expanded Access Program for Anti-TNF Chimeric Monoclonal Antibody (infliximab)’ and infliximab was provided by Schering-Plough