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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Background: 59–81% of patients given infliximab for Crohn's disease will respond. Although now in widespread use, little consensus exists regarding the optimal place in patient care. Recently developed guidelines have identified need for markers that predict response.

Aims: We aimed to identify markers of response to infliximab given for Crohn's disease.

Methods: Markers of response (defined at 4 weeks) were prospectively assessed in 74 infliximab-treated patients with Crohn's disease. Patients were followed-up to 1 year.

Results: Fifty-four of 74 (73%) patients responded. Univariate analysis identified that smokers were less likely to respond than non-smokers [P = 0.005, odds ratio (OR) 0.22]. Patients established on immunosuppression (P = 0.034, OR 7.31) and with isolated colonic disease (P = 0.042, OR 3.83) were more likely to respond. Multiple logistic regression confirmed smoking (P = 0.035, OR 0.24) and colonic disease (P = 0.035, OR 4.87) as independent markers of response. One-year relapse rates differed significantly between smokers and non-smokers (100% vs. 39.6%, P = 0.0026, relative risk 3.2) and between patients established on immunomodulators or not (58.0% vs. 92.8%, P = 0.0054, relative risk 2.6).

Conclusions: Smoking has a strong adverse effect on the response rates and maintenance of response to infliximab. Patients on immunomodulators have a more favourable short- and long-term response. These results have important implications for clinical practice.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Infliximab is a chimeric mouse/human monoclonal antibody to tumour necrosis factor α (TNFα). It is an effective treatment for fistulating and refractory inflammatory Crohn's disease, with response rates of 59–81%.1, 2 The drug has been widely used world-wide, but at present little consensus exists about its place in patient management. Maintenance treatment has been proposed; however, infliximab is expensive, requires intravenous infusion and is associated with adverse events including infusion reactions in 23% and infections requiring antibiotics in 30%.1 A question mark remains over the incidence of lymphoma following treatment with infliximab.3 Guidelines developed by the National Institute for Clinical Excellence (NICE) in England and Wales and the Health Technology Board for Scotland (HTBS) have suggested use in patients with severe Crohn's disease who are unresponsive to corticosteroids and immunomodulators, but have not advised use in patients with fistulating disease unless there is coexisting active luminal disease.4 With the implementation of the NICE guidelines, it is clear that UK prescribing practice differs considerably from that in Europe and North America. In addition, NICE and HTBS identified the need for markers predictive of response.

The identification of predictive factors may improve response rates, attenuate morbidity and allow cost-effective use of the drug. Clinical features, antibody status and laboratory and genetic markers have all been proposed as indicators of response to infliximab, but many have been implicated only in single studies. Smoking status has been associated with poor response in one North American cohort.5 The effect was seen in patients with refractory inflammatory disease but not in those with fistulating disease. At 4–6 weeks post-infusion 78% of smokers had responded as compared with 22% of non-smokers. Long-term response (defined as greater than 2 months) was seen in 59% of non-smokers as compared to 6% of smokers. These findings, however, were not confirmed in a large European study.6 Both studies identified the concomitant use of immunomodulators as beneficial in maximizing response. Recent evidence has confirmed the association of immunomodulation and longer duration of response, this being associated with a lower frequency of antibodies to infliximab and higher serum concentrations of infliximab 4 weeks post-infusion.7 Young age, Crohn's colitis6 high serum C-reactive protein (CRP)8 and low serum TNFα levels9 have also been associated with a good response, whereas a combination of serological markers [p-antineutrophil cytoplasmic antibody (ANCA) positive and anti-Saccharomyces cerevisiae antibody (ASCA) negative]10 has been associated with a poor response.

Genetic determinants of response to infliximab have been postulated due to the stability of non-response over time. An association of response and a TNF/lymphotoxin α (LTA) haplotype has been suggested,11 but NOD2/CARD15 genotype has not been found to influence response.12, 13 After initial optimism the polymorphism at position 308 within the promoter region of the TNF gene was found not to be associated with response.8 A number of other polymorphisms in the TNF, TNF receptor I and TNF receptor II do not appear to be associated with response.14

We have previously demonstrated efficacy of infliximab in a UK Crohn's disease population,15 but thus far no prognostic markers have been identified. We thus aimed to assess markers predictive of response to infliximab in the largest UK Crohn's disease cohort reported thus far.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Seventy-four consecutive patients with well characterized Crohn's disease were prospectively assessed. There were 42 females and 32 males with a median age at treatment of 34 years (IQR 23–42.5). All patients received infliximab (5 mg/kg) at the Western General Hospital, Edinburgh between June 1999 and June 2002. The diagnosis, as defined by the Lennard-Jones criteria,16 was established with radiological, endoscopic and histological methods. Patients were admitted for infusions of infliximab, an audit form was completed prospectively, and data were collected regarding demographic details, confirmation of diagnosis, previous surgery, disease details, smoking and alcohol consumption and medications taken. Clinical disease activity was assessed by the Harvey–Bradshaw index.17 Blood was taken for full blood count, serum albumin, erythrocyte sedimentation rate, C-reactive protein, ASCA and ANCA.

A smoker was defined as smoking more than five cigarettes per day for more than 6 months. Azathioprine therapy was considered established after duration of 3 months or more.

Sixty patients received infliximab for refractory inflammatory Crohn's disease and 14 for fistulating Crohn's disease. The median age at diagnosis was 25.2 years (interquartile range (IQR) 15.0–29.8). Anatomical distribution of affected bowel at the time of infliximab treatment comprised isolated ileal disease in 11, colonic disease in 25, ileocolonic disease in 26 and recurrent small bowel disease following ileostomy in 10. Forty patients had associated peri-anal disease and 36 had undergone previous intestinal resection. At the time of the infusion 21 patients were current smokers, all smoking in excess of 10 cigarettes per day, 16 were ex-smokers having given up in excess of 6 months previously and 34 had never smoked. Smoking data were not available on three patients. Forty-seven were taking oral prednisolone at infusion, 16 were established on azathioprine and two were established on methotrexate. Baseline clinical data on those with refractory and fistulating Crohn's disease are displayed in Table 1.

Table 1.  Baseline clinical data categorized by indication for infliximab treatment
ParameterRefractory CD (n = 60)Fistulating CD (n = 14)P -value
  1. CD, Crohn's disease. Data are expressed as median and inter-quartile ranges for continuous data and numbers of patients for binary data.

Age at infusion31.535.50.3
 (years)23–4229–57 
Sex (Males : Females)22 : 3811 : 40.011
Age at diagnosis2419.50.9
 (years)15–2912–36 
Anatomical distribution1010.4
Ileal alone1010.4
Colon alone2240.6
Ileocolon2440.5
Ileostomy450.005
Peri-anal disease29110.041
Smoking1740.9
Prednisolone4430.002
Azathioprine1420.5
Previous surgery2580.3

Patient selection

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

All patients who were treated for refractory Crohn's disease had previously been given at least one course of corticosteroids in an attempt to induce remission. In addition, an attempt to use immunosuppressive medications had been made. Patients who received infliximab were unresponsive to steroids, were unable to reduce steroid dose, or had a contraindication to the use of steroids. All had active disease at the time of infusion as defined by the Harvey–Bradshaw index. Patients who received infliximab for fistulating Crohn's disease had persistent fistulating disease unresponsive to conventional treatment.

The patients were assessed at the time of infusion and after 4 (refractory Crohn's disease) or 10 (fistulating Crohn's disease) weeks. Patients were thereafter followed prospectively for up to one year or until a relapse occurred.

At the time of treatment with infliximab, patients were initiated on immunomodulation if this was not already in place and no contraindications existed. When patients were intolerant of azathioprine either 6-mercaptopurine (1 mg/kg) or methotrexate (25 mg intramuscular [IM] for 12 weeks, subsequently 15–25 mg orally) was used.

Refractory Crohn's disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Patients with refractory Crohn's disease received a single infusion of infliximab. A response was defined as a reduction in the Harvey–Bradshaw index by more than 3 points. Remission was defined as a Harvey–Bradshaw index of 4 or less. A relapse was defined as an increase in the Harvey–Bradshaw index by more than 3 points. The commencement or increase in dose of oral steroids for symptom deterioration, re-infusion of infliximab for symptom deterioration and the need for surgery were also defined as a relapse.

Fistulating Crohn's disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Patients with fistulating disease received three infusions at 0, 2 and 6 weeks. A response of a fistula was defined as a 50% reduction in the number of draining fistulae as previously described.18 A fistula was defined as closed when it no longer drained despite gentle finger compression. A complete response was defined as the absence of any draining fistulae.

Statistics

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Results were entered into a Minitab statistical software package. For data regarding ages, comparisons were made using a two-sample t-test. For non-parametric data a Mann–Whitney U-test was used. A chi-squared test, with Yates' correction where appropriate, was used for the comparison of frequencies. The frequencies of relapse were analysed using a Kaplan–Meier survival curve. From this a survival proportion and standard error may be calculated.19 For the direct comparison of two curves the log rank test has been used. Stratification of the data set has been necessary. To give an indication of the magnitude of difference between the curves the relative risk was calculated by comparisons of the observed and expected frequencies of the events. To discriminate the influence of multiple independent variables, on relapse multiple regression analysis has been used.20 The data analysed are of different types and therefore standardization was performed prior to analysis. The r2 value of the individual values did not exceed 0.8 and therefore multicollinearity was avoided. To assess statistical significance a t-score was calculated to test the null hypothesis.

Response at 4 weeks

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Fifty-four of 74 patients responded (73.0%), 18 had no response and two, given the drug for steroid sparing, remained in remission. Forty-three patients (71.6%) given the drug for inflammatory disease responded and 12 (86%) treated for fistulating disease responded.

Prediction of response at 4 weeks: univariate analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

When both treatment indications are considered, those who smoked were less likely to respond to infliximab than those who did not {11/21 vs. 42/50, χ2 = 7.8, p = 0.005, odds ratio (OR) 0.22 [confidence interval (CI) 0.08–0.41)]}. A more favourable response was seen in patients established on azathioprine for longer than 3 months at infusion (15/16 vs. 39/56, χ2 = 4.5, P = 0.034, OR 7.31 (CI 3.34–10.31) (Figure 1) and in those with colonic disease distribution (χ2 = 4.1, P = 0.042, OR 3.83, CI 1.88–5.78). A trend towards a poorer response was seen in patients with peri-anal disease (χ2 = 2.9, P = 0.088, OR 0.37, CI 0.19–0.64) and ileal involvement (χ2 = 2.7, P = 0.095, OR 0.33, CI 0.19–0.59). Age at diagnosis, previous surgery, preinfusion disease activity, CRP and ASCA/ANCA status did not influence response rates (Table 2).

image

Figure 1. Graphical representation of the effect of smoking and the concurrent use of azathioprine on response rates to infliximab assessed at 4 weeks. White boxes represent patients who responded to the drug whereas black boxes represent those who did not.

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Table 2.  Clinical and laboratory parameters categorized for response
ParameterResponse (n = 54)No response (n = 18)P- value
  1. Data are expressed as median and inter-quartile ranges for continuous data and numbers of patients for binary data.

Age (years)33.531.50.5
24–4320–38 
Age at diagnosis23200.4
 (years)15–3014–26 
Colonic disease2330.042
Ileal disease650.082
Peri-anal disease26130.088
Smoking11100.005
Azathioprine > 3/121510.034
Previous surgery23110.3
Pre treatment HBI10110.4
7–128–15 
Haemoglobin (g/dL)120.01240.6
(111.0–131.5)(110.8–130.8) 
Platelets (× 106/mL)3473660.9
281–456305–430 
Erythrocyte sedimentation rate (ESR)29220.5
16–4610–44 
CRP (mg/L)19200.9
10–349–48 
Albumin (g/L)35370.4
31–4033–40 

In patients treated for inflammatory disease, smoking remained a poor prognostic marker (χ2 = 5.4, P = 0.021, OR 0.24, CI 0.10–0.30) and azathioprine approached but did not achieve statistical significance (χ2 = 3.5, P = 0.061, OR 6.3, CI 3.2–11.8). In this group peri-anal disease was seen more frequently in non-responders (P = 0.043). Low numbers of non-responding patients with fistulating Crohn's disease prevented meaningful analysis of this group.

Response at 4 weeks: multiple logistic regression

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

All variable with a P-value of 0.1 or less on univariate analysis were entered in to a multiple logistic regression model. Smoking (P = 0.035, OR 0.24, CI 0.06–0.91) and colonic disease distribution (P = 0.035, OR 4.87, CI 1.12–21.24) were identified as independent predictive factors of response to infliximab (Table 3).

Table 3.  Multiple logistic regression analysis for response to infliximab at 4 weeks
ParameterP-valueOdds ratio95% CI
Smoking0.0350.240.06–0.91
Colonic disease0.0354.871.12–21.24
Peri-anal disease0.0640.300.08–1.07
Ileal disease0.5970.570.07–4.48
Azathioprine0.5701.680.28–9.94

Response at 1 year

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

Responding patients were followed prospectively for up to 1 year or until relapse. Of the 54 responding patients, 29 had relapsed, 11 had not relapsed at 1 year, 10 had shorter follow-up periods but had not relapsed and four had defaulted follow-up. Overall the proportion of patients that initially responded who had a continued response at 1 year was 11/40 (27.5%). Factors predicting response at 4 weeks were subsequently assessed with respect to the persistence of response at 1 year. Kaplan–Meier survival curve analysis demonstrated that smoking patients relapsed more frequently than non-smoking patients (χ2 = 9.0, P = 0.0026, relative risk 3.2) and those established on azathioprine or methotrexate prior to or after the infusion relapsed less frequently (χ2 = 7.7, P = 0.0054, relative risk 2.6). The anatomical distribution of disease, however, did not affect the relapse rate up to 1 year (χ2 = 1.36, P = 0.24, relative risk 1.6) (Figure 2).

image

Figure 2. Kaplan–Meier survival curve analysis categorized for smoking status (a) and immunomodulation (b) Smokers relapsed more frequently than non-smokers (χ2 = 9.0, P = 0.0026, relative risk 3.2), and patients on immunomodulators relapsed less frequently than those who were not (χ2 = 7.7, P = 0.0054, relative risk 2.6).

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References

These findings have potentially important implications for clinical practice. Overall, we have demonstrated a response rate of 73% when assessed at 4 weeks, with 71.6% of patients treated for refractory luminal Crohn's disease responding and 86% of those treated for fistulating disease responding. This is the first study in Europe to confirm that smoking has a strong adverse effect on short-term response rates to infliximab. In addition we have confirmed that the prior use of azathioprine has a beneficial effect on the response rates, and we have also demonstrated better response rates in patients with isolated colonic disease. Smoking status and the use of immunomodulators remain important factors in the maintenance of response to infliximab in patients followed up to 1 year post-treatment. This is the largest UK cohort described thus far, reflecting the high prevalence of disease in Scotland.

Smoking is arguably the most important environmental influence on susceptibility and disease behaviour in Crohn's disease. Smoking predisposes to Crohn's disease21 and is associated with greater need for immunomodulators,22 more frequent surgery,22 more rapid recurrence post-resection23 and a greater overall mortality.24 Cosnes et al. also suggested that some of the detrimental effects of smoking might be counteracted by immunomodulation.22 More recent data have suggested that smoking cessation25 may improve the clinical course of Crohn's disease. The presented data regarding smoking have remarkable similarity to those of Parsi et al.5 The strength of the effect is emphasized further by combining the data sets (P < 0.0001, χ2 = 19.3, OR 0.17, CI 0.08–0.24). There are, however, confounding data; a larger European study did not find an association between non-response and smoking.6 Perhaps the most plausible explanation for this apparent discrepancy is the definition of smoking. Both the current study and that of Parsi et al. have used a definition of greater than five cigarettes per day for greater than 6 months. The exact definition of smoking in the European study is not clear, but their data may have been confounded by a number of relatively light or even intermittent smokers. Similarly, the observed results may be a factor of relatively heavy smoking. The mechanism whereby smoking habit influences susceptibility and disease behaviour in inflammatory bowel disease remains under detailed investigation:26 effects on specific and innate immunity, intestinal barrier function, vasculature and enteric nervous system have all been ascribed to nicotine, but at present it remains unclear if it is nicotine or one of the other 4000 components of cigarette smoke that is implicated in the detrimental effects on Crohn's disease. Thus, the safety and advisability of nicotine patches, which may help smoking cessation in patients with Crohn's disease, must be regarded as uncertain.

The data with regard to concomitant immunomodulators are also provocative. We have confirmed the beneficial effect of concurrent immunomodulation; patients established on azathioprine for greater than 3 months had a response rate of 93% at 4 weeks. In addition, we have also shown the importance of maintenance treatment with a continued response in 40% of patients on immunomodulation compared to 7% in those not on a maintenance agent. This observation has been noted previously: Rutgeerts et al.27 noted a trend towards a better response in those on azathioprine, and this has also been seen in two more recent studies.5, 6 There are clear parallels with experience in rheumatoid arthritis, for which the benefits of combination treatment with immunosuppressants have been known for some time.28, 29 Concomitant immunosuppression has also recently been associated with fewer antibodies against infliximab and higher serum concentrations of infliximab 4 weeks following an infusion.7 Antibodies against infliximab were associated with a higher frequency of infusion reactions and fewer days until relapse. Although a subsequent infusion reaction may be prevented by pre-treatment with hydrocortisone (and this was associated with higher infliximab concentrations), this did not correspond to a longer time to relapse. We feel that patients with steroid-refractory Crohn's disease should be initiated on immunomodulation at an early stage and the drug continued to maximize response to infliximab. It is of some interest that in the present study, disease that has previously been resistant to immunomodulation can be maintained with these agents following treatment with infliximab. The ACCENT I trial examined infliximab re-treatment to maintain remission in Crohn's disease.1 Approximately 50% of patients had a continued clinical response at 1 year, a similar figure to the data seen above. Only one third of patients were maintained on immunomodulators.

We also identified isolated colonic disease as a favourable prognostic marker on univariate analysis with respect to short-term response and this was confirmed on multivariate analysis. Vermeire et al. also demonstrated a better response in patients with colonic disease but in their decision tree analysis this was not felt to be important. It was not, however, a determinant of long-term response in our study. Again, the mechanism of this association is not clear but a genetic influence is possible. Safety and toxicity of infliximab, both short-term and long-term remain important issues. Patients established on immunomodulators experience a lower rate of infusion reactions,1, 30 and although children may have a lower rate of infusion reactions, a delayed second infusion is associated with more frequent reactions.31 There may be an additive effect of corticosteroids and immunomodulators in preventing infusion reactions.1 In the presented data we experienced seven infusion reactions; four required the infusion to be stopped.

Other adverse events associated with infliximab include infections, which require antibiotics in one third of patients.1 More recent data have suggested that anti-TNFα therapy may be associated with an increased incidence of lymphoma; an initial report identified 26 cases in patients receiving infliximab and etanercept for all indications.3 A further 68 cases have been reported to the United States Food and Drug Administration. The majority of patients received the drug for indications other than Crohn's disease, but clearly further work is required to identify those at risk of developing this and other related complications and emphasizes the need for the most clinically effective use of the drug.

In summary, the present data demonstrate rates of response comparable with other studies in both fistulating and non-fistulating disease. We have identified two factors directly influencing short-term and long-term response which may be of direct use in clinical practice: smoking and concurrent immunosuppression. It is of real interest that initially refractory disease that has responded to infliximab may subsequently be maintained with concomitant agents. These data may help in the revision of guidelines for the use of infliximab in Crohn's disease in the United Kingdom.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Methods
  7. Patient selection
  8. Refractory Crohn's disease
  9. Fistulating Crohn's disease
  10. Statistics
  11. Results
  12. Response at 4 weeks
  13. Prediction of response at 4 weeks: univariate analysis
  14. Response at 4 weeks: multiple logistic regression
  15. Response at 1 year
  16. Discussion
  17. References
  • 1
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 1902; 0: 15419.
  • 2
    Targan SR, Hanauer SB, Van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997; 337: 102935.
  • 3
    Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46: 31518.
  • 4
    National Institute for Clinical Excellence (NICE). Guidance on the use of infliximab for Crohn's disease 2002; 40: 1.
  • 5
    Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology 2002; 123: 70713.
  • 6
    Vermeire S, Louis E, Carbonez A, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease. Am J Gastroenterol 2002; 97: 235763.
    Direct Link:
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    Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003; 348: 6018.
  • 8
    Louis E, Vermeire S, Rutgeerts P, et al. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with −308 TNF gene polymorphism. Scand J Gastroenterol 2002; 37: 81824.
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    Martinez-Borra J, Lopez-Larrea C, Gonzalez S, et al. High serum tumor necrosis factor-alpha levels are associated with lack of response to infliximab in fistulizing Crohn's disease. Am J Gastroenterol 2002; 97: 23506.
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    Esters N, Vermeire S, Joossens S, et al. Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease. Am J Gastroenterol 2002; 97: 145862.
    Direct Link:
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    Taylor KD, Plevy SE, Yang HY, et al. ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease. Gastroenterology 2001; 120: 134755.
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    Vermeire S, Louis E, Rutgeerts P, et al. NOD2/CARD15 does not influence response to infliximab in Crohn's disease. Gastroenterology 2002; 123: 10611.
  • 13
    Mascheretti S, Hampe J, Croucher PJ, et al. Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials. Pharmacogenetics 2002; 12: 50915.
  • 14
    Mascheretti S, Hampe J, Kuhbacher T, et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab. Pharmacogenomics J 2002; 2: 12736.
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