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Keywords:

  • ulcerative colitis;
  • UC;
  • infliximab;
  • IFX;
  • response;
  • outcome;
  • predictors;
  • ASCA;
  • pANCA

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

Background: Our objective is to report the outcome of infliximab (IFX) in ulcerative colitis (UC) patients from a single center and to identify predictors of early clinical response.

Methods: The first 100 UC patients (45 female; median age, 37.9 years) who received IFX at a single center were included. Eighty-four patients received 5 mg/kg IFX, and 37 patients received a 3-dose IFX induction at weeks 0, 2, and 6. The Mayo endoscopic subscore, assessed by sigmoidoscopy before inclusion, was 1, 2, and 3 in 5%, 52%, and 43% of patients, respectively. Sixty percent had pancolitis, 63% were on concomitant immunosuppressive therapy, 9% were active smokers, 64% had C-reactive protein ≥5 mg/dL, and 44% were pANCA+/ASCA−. Five patients received IFX because of severe acute colitis refractory to intravenous corticosteroids.

Results: Early complete and partial clinical responses were observed in 41% and 24% of patients. Patients with early clinical response were significantly younger than nonresponders (median age, 35.7 versus 41.6 years, P = 0.041). Patients who were pANCA+/ASCA− had a significantly lower early clinical response (55% versus 76%; odds ratio [OR] = 0.40 (0.16–0.99), P = 0.049). Concomitant immunosuppressive therapy and the use of an IFX induction scheme did not influence early clinical response. Only 1 of 5 patients who received IFX for acute steroid-refractory colitis required colectomy within 2 months.

Conclusions: IFX is an efficient therapy in UC, as shown by 65% early clinical response. A pANCA+/ASCA− serotype and an older age at first IFX infusion are associated with a suboptimal early clinical response.

(Inflamm Bowel Dis 2006)

Ulcerative colitis (UC) is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon, as well as rectal bleeding, diarrhea, and abdominal pain. Most patients with UC can be treated successfully with 5-aminosalicylates, corticosteroids, and/or immunomodulators, such as azathioprine and 6-mercaptopurine.1 Approximately 15% of UC patients will have a severe attack requiring hospitalization during their illness,2 and are treated primarily with high doses of corticosteroids intravenously.3–5 Despite intravenous corticosteroids, severe attacks have a high colectomy rate varying from 38% to 47%.4, 5 In addition, cyclosporine has been validated as an efficacious treatment in severe UC,6, 7 but is frequently associated with toxicity8 and only seems to postpone the inevitable colectomy.9, 10

In contrast to Crohn's disease (CD), UC has historically been considered a T-helper 2-driven disease, with a less prominent role for tumor necrosis factor (TNF). However, 2 lines of evidence suggest an important role of TNF in UC pathogenesis. First, several investigators found increased TNF levels in mucosal tissue, stools, colon perfusates, rectal dialysate, serum, and urine of UC patients with active colitis.11–14 Second, CD571, a monoclonal antibody against human TNF-α, significantly improved UC-like colitis in the cotton top tamarin.15

The initial open label and small randomized-controlled clinical trials with infliximab16, 17 resulted in conflicting data, based on the lack of a placebo-controlled arm, a lack of power, or the different population studied in each trial (steroid-refractory versus patients with moderate-to-severe UC).

The randomized, double-blind, multi-center placebo-controlled ACT1 and ACT2 trials, however, clearly showed a significant benefit of infliximab (IFX) in patients with moderate-to-severe active UC.18 Patients received an induction scheme with placebo or IFX 5 or 10 mg/kg body weight at weeks 0, 2, and 6 and maintenance therapy thereafter (placebo or IFX every 8 weeks), for a total of 22 weeks (ACT2) or 46 weeks (ACT1). A clinical response at 8 weeks was seen in 29%–37% for placebo versus 64%–69% for IFX 5 mg/kg versus 61%–69% for IFX 10 mg/kg (P < 0.001). At 30 and 54 weeks the clinical response rates remained significant better in the IFX-treated group. Furthermore, patients receiving IFX had significant higher clinical remission rates, mucosal healing and they were more able to stop corticosteroids.

The only randomized-controlled trial in patients with severe steroid-refractory UC so far, by Jarnerot et al,19 reported significantly lower colectomy rates 3 months after IFX (29% versus 67%, P = 0.017). Furthermore, the use of infliximab did not have any effect on postoperative complications.

Despite a clear benefit of IFX in UC patients in the ACT1 and ACT2 trials and the study by Jarnerot et al, questions about long-term safety, immunogenicity and cost-effectiveness remain of current interest. Because, as in CD, a subset of UC patients clearly do not respond to IFX, it is important to identify predictors of response to this rather expensive and potentially harmful drug, to allow careful selection of patients.

The aim of our study was to study clinical outcome in a consecutive series of 100 UC patients from a single referral center, and to identify possible predictors of short term clinical and endoscopic response to IFX.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

Patient Population

The first 100 UC patients (female-to-male ratio, 45/55) who received IFX were included in this study. Diagnoses of UC were established after thorough clinical, radiologic, endoscopic, and histologic examination.20 Information regarding the presence of 3 common CARD15 polymorphisms (by PCR-RFLP) and antibodies directed against the unidentified nuclear lamina protein present in neutrophils (pANCA) and antibodies against mannose epitopes from the yeast Saccharomyces cerevisiae (ASCA) (by ELISA) was available.

All patients received their first infusion with IFX between January 2000 and February 2006 at our tertiary referral center. The median age (interquartile range or IQR) at first IFX infusion was 37.9 (27.3–51.4) years. All patients' characteristics are mentioned in Table 1. The median duration (IQR) of disease before first IFX infusion was 5.8 (2.1–13.8) years.

Table 1. Patients' Characteristics
Female/Male (%)45/55 (45/55)
Median age (range) at diagnosis27.6 (8.2–76.5) years
Median duration (range) of disease5.8 (0.3–35.2) years
Median age (range) at first IFX infusion37.9 (9.1–81.9) years
Extent of inflammation 
 Proctitis (%)2/100 (2)
 Left-sided colitis (%)38/100 (38)
 Pancolitis (%)60/100 (60)
Mayo endoscopic subscore before IFX 
 Mayo 1 (%)4/85 (5)
 Mayo 2 (%)45/85 (53)
 Mayo 3 (%)36/85 (42)
Histologic grade of inflammation 
 Grade 0 (%)0/69 (0)
 Grade 1 (%)0/69 (0)
 Grade 2 (%)14/69 (20)
 Grade 3 (%)20/69 (29)
 Grade 4 (%)21/69 (31)
 Grade 5 (%)14/69 (20)
C-reactive protein ≥5 mg/dL at first IFX (%)58/91 (64)
Active smoking at first IFX (%)8/91 (9)
Presence of pANCA and ASCA at first IFX (%) 
 pANCA-/ASCA−47/99 (47)
 pANCA+/ASCA−44/99 (44)
 pANCA-/ASCA+5/99 (6)
 pANCA+/ASCA+3/99 (3)
Concomitant oral steroids (%)50/100 (50)
Concomitant immunosuppressive therapy (%)63/100 (63)
Severe refractory UC requiring hospitalization for IV steroids (%)5/100 (5)
Number of CARD15 mutations 
 None (%)75/97 (77)
 One (%)20/97 (21)
 Two (%)2//97 (2)
IFX dose 
 5 mg/kg body weight (%)84/100 (84)
 10 mg/kg body weight (%)16/100 (16)
Induction scheme (%)37/100 (37)

Forty-two patients previously participated in the ACT1 trial.18 Fifteen of them were randomized to 10 mg IFX per kg body weight; 15 others received 5 mg IFX per kg. For these 30 patients the ACT1 data were reused in this trial. The remaining 12 UC patients had been randomized to placebo treatment during the ACT1 trial but received open-label 5 mg IFX per kg body weight during follow-up. One patient received 10 mg IFX per kg body weight, outside of the ACT1 trial. In total, 37 patients received an IFX induction scheme, with IFX at weeks 0, 2 and 6.

Most included UC patients had moderate-to-severe disease and were not hospitalized for the IFX infusion. Only 5 UC patients had severe refractory UC requiring hospitalization and, before the IFX infusion, failed intravenous corticosteroids (4 patients) or both intravenous corticosteroids and cyclosporine (1 patient). During hospitalization these patients were constantly monitored by both gastroenterologists and abdominal surgeons because they were in danger of needing urgent colectomy.

All individuals gave informed consent, and this study was approved by the local ethics committee of the Catholic University of Leuven.

Definitions of Response

Clinical and endoscopic responses to IFX were evaluated after 4 weeks in patients who received 1 single infusion with IFX and after 10 weeks in patients who received the induction scheme (IFX at weeks 0, 2, and 6). In patients who did not participate in the ACT1 trial, clinical and endoscopic data were assessed retrospectively through chart review.

Clinical response was defined as complete if there was absence of diarrhea and blood, and partial if there was marked clinical improvement but still persistent rectal blood loss. To assess mucosal healing, endoscopy was performed in 56 of 100 patients both before IFX and 4–10 weeks after the first IFX infusion. In accordance with the ACT trials, mucosal healing was defined as a Mayo endoscopic subscore of 0 or 1, and was only assessed in patients with a Mayo endoscopic subscore of at least 2 at inclusion.

Predictors of Response

Besides demographic characteristics as gender, age at diagnosis, duration of disease before IFX and age at first IFX infusion, we also assessed parameters of disease severity. Extent of inflammation was defined as proctitis, left-sided colitis, or pancolitis, using the recently published Montreal classification.21 In 84 of 100 UC patients endoscopic features before IFX were scored using the Mayo subclassification.22

In 69 UC patients, we histologically assessed the grade of inflammation before IFX, using a previously reported grading scale by Geboes et al.23 If there were only architectural changes the histologic inflammation was graded 0. Features of chronic inflammatory infiltrate were graded 1, infiltration of the lamina propria with neutrophils or eosinophils was graded 2, cryptitis was graded 3, and crypt destruction was graded 4. Grade 5 was assigned to biopsies with erosions, ulcerations or recovering epithelium with adjacent inflammation.

In 87 UC patients, serum samples were taken at the moment of first IFX infusion and ELISA was performed for both pANCA and ASCA antibodies. Since the combination of pANCA and ASCA has the highest specificity, we looked for the predictive role of this combination.

Other variables considered were the dose of first IFX (5 or 10 mg/kg body weight), the use of an IFX induction scheme (weeks 0, 2, and 6), C-reactive protein levels at first IFX infusion, smoking status, and concomitant therapy with corticosteroids or immunomodulators (azathioprine or methotrexate).

Statistical Analysis

All statistical tests were performed with the SPSS 12.0 statistical software package (SPSS, Chicago, IL). These tests included χ2, Fisher-exact, Mann-Whitney, Spearman-rank correlation and backward Wald multiple binary logistic regression. Possible predictors of response with P < 0.1 in univariate analysis, were examined in multivariate analysis to define independent contribution of each of the possible factors. The threshold for statistical significance was predefined as a P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

Response Rates

Overall, 65% of 100 UC patients treated with IFX showed early clinical response. In more detail, 41% patients had a complete response, 24% had a partial response, and 35% lacked a clinical response. For further statistical analyses patients with both complete and partial clinical response were taken together as early clinical responders.

For early endoscopic response, endoscopy was repeated in 56 patients who had a Mayo endoscopic subscore of at least 2 at inclusion. Mucosal healing 4 or 10 weeks after first IFX infusion was determined in 57% of these patients. In detail, 9 and 23 patients had a Mayo endoscopic subscore of, respectively, 0 and 1. An example of complete mucosal healing after 4 weeks is shown in Figure 1. As shown in Figure 2, 19 % of 16 clinical nonresponders, 53% of 15 partial clinical responders and 84% of 25 complete clinical responders, showed mucosal healing after IFX (P < 0.001).

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Figure 1. Mucosal healing 4 weeks after a single infliximab infusion for moderate-to-severe ulcerative colitis. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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thumbnail image

Figure 2. Mucosal healing in function of early clinical response to infliximab in 56 UC patients.

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Five patients received IFX during hospitalization and were in danger of colectomy because they did not respond to IV corticosteroid. Three patients, including the one who also received IV cyclosporine, showed complete clinical response 4 weeks after the first IFX infusion. One patient improved significantly after a second IFX infusion. One patient needed a colectomy within 2 months after the first IFX infusion.

During a median follow-up of 2.7 (range, 0.4–6.4) years, 11 of 100 UC patients needed a colectomy. One of these patients failed IFX after more than 4 years. All other patients had their colectomy within the first year. Six (55%) had received an induction scheme of IFX, and 4 (36%) had received maintenance therapy with IFX every 8 weeks.

Predictors of Early Clinical Response

Results of a univariate analysis for predictors of early clinical response are shown in Table 2. Patients who had early clinical response were significantly younger compared to nonresponders (median age (IQR) 35.7 (25.2–48.6) years versus 41.6 (30.6–57.3) years, Mann-Whitney U test, P = 0.041). Age at diagnosis (P = 0.093) and duration of disease before first IFX infusion (P = 0.994) were not associated with early clinical response. Furthermore, patients who were pANCA+/ASCA− had a lower early clinical response (55% versus 76%, OR = 0.40 (0.16–1.00), P = 0.047) (Fig. 3). The presence of pANCA alone did not influence clinical outcome.

Table 2. Univariate Analysis of Possible Predictors of Early Clinical Response to IFX
VariableP-valueOdds Ratio95% CI
Female gender0.2461.640.71–3.80
Age at diagnosis0.093  
Duration of disease0.994  
Age at first IFX0.041  
Pancolitis0.3921.440.63–3.31
Mayo endoscopic subscore 30.5940.780.31–1.94
Histologic grade of inflammation0.845  
C-reactive protein ≥5 mg/dL0.8090.890.36–2.25
Active smoking0.4320.460.11–1.97
pANCA+/ASCA−0.0470.400.16–1.00
Concomitant oral steroids0.5290.770.34–1.75
Concomitant immunosuppressive therapy0.3970.690.29–1.64
Severe refractory UC requiring hospitalization for IV steroids1.0000.800.13–5.02
Presence of CARD15 mutations0.4471.500.53–4.29
IFX 10 mg/kg body weight0.1700.470.16–1.40
IFX induction scheme0.9830.990.42–2.32
thumbnail image

Figure 3. Early clinical response to infliximab in function of serologic markers in 87 UC patients. Serum was taken before first infliximab infusion.

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Based on the outcome of the univariate analyses (P < 0.1), age at diagnosis, age at first IFX infusion and pANCA+/ASCA− were included in the multivariate analysis. The pANCA+/ASCA− serotype came out as the only independent variable associated with suboptimal early clinical response to IFX (55% versus 76%, OR 0.40 (0.16–1.00), P = 0.049).

We did not find a significant correlation between endoscopic and histologic findings, probably due to sampling errors (Spearman-rank, n = 69, r = 0.036, P = 0.770). Endoscopic and histologic findings before IFX, however, did not predict early clinical response. Also the use of an induction scheme with IFX (weeks 0, 2 and 6) had no influence on treatment outcome (OR = 0.99 (0.42–2.32), P = 0.983).

Because endoscopy was not performed systematically in all patients, we did not look into predictors of mucosal healing. It was obvious that endoscopy will be performed more often in patients with no clinical response or only partial clinical response, and analyzing these data retrospectively would encounter an important bias.

Finally, we could not find any independent predictors of colectomy after IFX infusion. But, patients with early clinical response to IFX had a significant lower colectomy rate during a median follow-up of 2.7 years (5% versus 23%, OR = 0.16 (0.04–0.66), P = 0.015).

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES

As shown in the recent placebo-controlled multicenter ACT1 and ACT2 trials, IFX is an effective treatment in patients with moderate to severe UC.18 In the present work, we report similar results in a cohort of 100 UC patient from a single tertiary referral center. Short-term complete and partial clinical response was observed, respectively, in 41% and 24% of patients. Furthermore, a pANCA+/ASCA− serotype and an older age at first IFX infusion were associated with a less favorable outcome. The use of an IFX induction scheme (weeks 0, 2 and 6) had no influence on short-term clinical response.

Although IFX has been proved effective in both CD and UC, a subset of patients clearly do not respond. In the ACT1 and ACT2 trials, for example, 31 to 39% of patients treated with IFX did not show clinical response after 8 weeks.18 Identifying predictors of response to IFX is an important issue, as it might help in carefully selecting patients who will benefit this more expensive and potential harmful therapy. In CD, some clinical, serologic, and genetic predictors of early response to IFX have been identified,24 but up to now, this has not been the case for IFX treatment in UC.

We found an independent association between the UC-associated serotype pANCA+/ASCA− and a suboptimal early clinical response to IFX (55% versus 76%, OR = 0.40 (0.16–1.00), P = 0.049). Interestingly, similar finding have been suggested in CD. Taylor et al25 reported lower response to IFX in CD patients who were pANCA positive. Our own group also found lower response rates in CD patients with refractory intestinal disease carrying the pANCA+/ASCA− serotype. This association, however, lacked significance (P = 0.067), probably because only 10 of 183 CD patients carried this specific serotype.26 In contrast, Arnott et al27 did not find an association between serotype and IFX response in a smaller heterogeneous cohort of 74 IFX treated CD patients. We should note, however, that although the early clinical response rate was significantly lower in patients with the pANCA+/ASCA− serotype, it was still 55%. Indicating that also in these patients IFX could be administrated in an appropriate clinical setting.

Of interest, 6 UC patients in our cohort had a CD-like pANCA−/ASCA+ serology. Reanalysis of the clinical and histologic findings confirmed the diagnosis of UC.

Furthermore, in univariate analysis, we found a significant association between younger age at first IFX infusion and favorable early clinical response (median age (IQR) 35.7 (25.2–48.6) years versus 41.6 (30.6–57.3) years, Mann-Whitney U test, P = 0.041). This finding was independent of age at diagnosis and disease duration before first IFX infusion, but not from the serotype. In a previously reported paper, similar data were found in a Belgian cohort of CD patients who received IFX for refractory luminal (n = 137) or fistulizing (n = 103) disease.28 Two other papers from the United Kingdom and the United States, however, did not find such association, in a smaller cohort of CD patients of 74 and 100 CD patients, respectively.27, 29

Concomitant immunosuppressive therapy with azathioprine or methotrexate did not influence early clinical response in our cohort of UC patients. However, this does not exclude an influence on the long run. In CD, several studies showed a clear benefit of concomitant immunosuppressive therapy in patients with refractory luminal disease.28, 29

There was no different early clinical outcome after application of an induction scheme with IFX at weeks 0, 2, and 6 or a single infusion with IFX. Up to now, the randomized clinical trials with IFX in UC, only used the induction scheme in all their patients.18 This has become a common practice, mainly to reduce immunogenicity, and not to improve efficacy. In the ACCENT 1 trial, for example, the clinical benefit of 3 infusions over 1 single infusion was only 13%.30 Further studies, including long term responses, are necessary to conclude on these finding.

Because only one-half of the UC patients included in this study underwent an endoscopic evaluation, we were unable to conclude firmly on predictors of early mucosal healing.

During a median (IQR) follow-up of 2.7 (range, 0.4–6.4) years, we did not find predictors of colectomy, but only 11% of the 100 UC patients failed medical therapy. Longer follow-up is undertaken. Interestingly, from the 5 patients who received IFX for severe corticosteroid-refractory disease only 1 patient did not show response to IFX and needed a colectomy within 2 months.

In conclusion, IFX is an efficient therapy in UC. Patients with a pANCA+/ASCA− serotype had a significant lower clinical response 4 to 10 weeks after the IFX administration, but this was still 55%. Concomitant immunosuppressive therapy and the use of an induction scheme with IFX at weeks 0, 2 and 6, did not influence early clinical response.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. CONCLUSIONS
  6. REFERENCES
  • 1
    Hanauer SB. Medical therapy for ulcerative colitis 2004. Gastroenterology. 2004; 126: 15821592.
  • 2
    Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut. 1963; 41: 299315.
  • 3
    Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. BMJ. 1955;: 10411048.
  • 4
    Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet. 1974; 1: 10671070.
  • 5
    Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology. 1985; 89: 10051013.
  • 6
    Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994; 330: 18411845.
  • 7
    Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999; 340: 13981405.
  • 8
    Sandborn WJ. Cyclosporine in ulcerative colitis: state of the art. Acta Gastroenterol Belg. 2001; 64: 201204.
  • 9
    Campbell S, Travis S, Jewell D. Cyclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol. 2005; 17: 7984.
  • 10
    Moskovitz DN, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol. 2006; 4: 760765.
  • 11
    Hadziselimovic F, Emmons LR, Gallati H. Soluble tumour necrosis factor receptors p55 and p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease. Gut. 1995; 37: 260263.
  • 12
    Guimbaud R, Bertrand V, Chauvelot-Moachon L, et al. Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis. Am J Gastroenterol. 1998; 93: 23972404.
    Direct Link:
  • 13
    Nielsen OH, Gionchetti P, Ainsworth M, et al. Rectal dialysate and fecal concentrations of neutrophil gelatinase-associated lipocalin, interleukin-8, and tumor necrosis factor-alpha in ulcerative colitis. Am J Gastroenterol. 1999; 94: 29232928.
  • 14
    Tsukada Y, Nakamura T, Iimura M, Iizuka BE, Hayashi N. Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis. Am J Gastroenterol. 2002; 97: 28202828.
    Direct Link:
  • 15
    Watkins PE, Warren BF, Stephens S, Ward P, Foulkes R. Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha. Gut. 1997; 40: 628633.
  • 16
    Sands BE, Tremaine WJ, Sandborn WJ, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis. 2001; 7: 8388.
  • 17
    Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut. 2003; 52: 9981002.
  • 18
    Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005; 353: 24622476.
  • 19
    Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005; 128: 18051811.
  • 20
    Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol. 1989; 170( Suppl): 26.
  • 21
    Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19 Suppl A: 536.
  • 22
    Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987; 317: 16251629.
  • 23
    Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lofberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000; 47: 404409.
  • 24
    Su C, Lichtenstein GR. Are there predictors of Remicade treatment success or failure? Adv Drug Deliv Rev. 2005; 57: 237245.
  • 25
    Taylor KD, Plevy SE, Yang H, et al. ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease. Gastroenterology. 2001; 120: 13471355.
  • 26
    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: 14581462.
    Direct Link:
  • 27
    Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn's disease. Aliment Pharmacol Ther. 2003; 17: 14511457.
  • 28
    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: 23572363.
    Direct Link:
  • 29
    Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology. 2002; 123: 707713.
  • 30
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359: 15411549.