- Citado por SciELO
versión impresa ISSN 1130-0108
Rev. esp. enferm. dig. vol.96 no.6 jun. 2004
Predictors of response to infliximab in patients with fistulizing Crohn's disease
M. Luna-Chadid, J.L. Pérez Calle1, J.L. Mendoza2, M. I. Vera3, A. F. Bermejo4, F. Sánchez5, A. López San Román4, C. Froilán6,
V. González-Lara1, J. García-Paredes2, I. Fernández-Blanco6, L. Abreu3, B. Casis5, J. A. Solís Herruzo5, J.P. Gisbert and J. Maté-Jiménez
Hospital de La Princesa. 1Hospital Gregorio Marañón. 2Hospital Clínico. 3Hospital Puerta de Hierro. 4Hospital Ramón y Cajal.
5Hospital Doce de Octubre. 6Hospital La Paz. Madrid, Spain.
Objective: to evaluate the efficacy and toxicity of infliximab for the treatment of fistulizing Crohn's disease.
Methods: consecutive patients with fistulizing Crohn's disease receiving infliximab were prospectively enrolled. Partial response was defined as a reduction of 50% or more from base-line in the number of draining fistulae. Complete response was defined as the closure of all fistulae. The influence of different variables on the efficacy of infliximab was evaluated.
Results: 108 patients were included. The disease was inflammatory plus fistulizing in 18% and only fistulizing in 82%. After the third infusion of infliximab the response was partial in 26% and complete in 57%. Response (%) rates (partial/complete) depending on fistula location were: enterocutaneous (25/68%), perianal (35/60%), rectovaginal (36/64%), and enterovesical (20/40%). None of the studied variables (including concomitant immunosuppressive therapy) correlated with efficacy of infliximab in the multivariate analysis. Incidence of adverse effects (21%) depending on the dose of infliximab was: first dose (5.6%), second (7.4%), and third (11.1%).
Conclusions: infliximab is an efficacious treatment for fistulizing Crohn's disease. Partial response was achieved in approximately one third of the patients, and complete response in more than half. No studied variable was predictive of response. Adverse effects were relatively infrequent and mild.
Key words: Crohn's disease. Inflammatory bowel disease. Infliximab. Fistulizing Crohn's disease. Fistula. Treatment.
Luna-Chadid M, Pérez Calle JL, Mendoza JL, Vera MI, Bermejo AF, Sánchez F, López-San Román A, Froilán C, González-Lara V, García-Paredes J, Fernández-Blanco I, Abreu L, Casis B, Solís Herruzo JA, Gisbert JP, Maté-Jiménez J. Predictors of response to infliximab in patients with fistulizing Crohn's disease. Rev Esp Enferm Dig 2003; 96: 379-384.
Financial Support: This work was supported in part by grants C03102 (to RMO) and C03101 (to FSM) from the Instituto de Salud Carlos III.
Correspondencia: J. Maté. Servicio de Enfermedades Digestivas. Hospital Universitario La Princesa. Diego de León, 62. 28006 Madrid
Infliximab was approved by the Food and Drug Administration in 1998 as a 3-dose regimen for the treatment of fistulizing Crohn's Disease (CD) (1). Treatment requires hospitalization, is expensive and is associated with severe side effects, including infusion reactions and infectious complications (2,3). In addition, the mean duration of response to medication is 2-3 months, (3-5) often requiring retreatment at regular intervals.
The clinical and demographic parameters that determine the response or lack of response remain unknown. Some studies suggest a positive correlation between the concurrent use of immunosuppressive agents and response to infliximab in patients with inflammatory CD (6-8). However, the concurrent administration of an immunomodulator showed no short-term advantage in fistulizing CD (2,3,7,8).
Identifying predictors of response to infliximab would be of great benefit in the selection of patients for this treatment, and this could in turn affect cost-related issues. The aim of this study was to evaluate the efficacy and to identify predictors of response to infliximab in fistulizing CD.
Study subjects. All the consecutive CD patients who were treated with intravenous infusions of infliximab 5 mg/kg at seven University Hospitals in Madrid, from October 1999 to March 2001, were evaluated in a prospective cohort study.
Inclusion criteria. a) age >18 and <65 years; b) CD patients with one or more open fistulas; c) patients receiving medications for fistulizing CD (azathioprine/6-mercaptopurine, metronidazole, ciprofloxacin) for 6 months or longer; d) three infliximab infusions completed at 0, 2, and 6 weeks; and e) at least 4 weeks of post-infusion follow-up from the third infliximab infusion.
Exclusion criteria. a) previous treatment with infliximab; b) serious infection, including tuberculosis; c) positive pregnancy test; and d) serious allergy history.
Study approval was granted by the respective Ethics Committees of the participating institutions. All patients gave written informed consent before study entry.
Data collection. The following data were collected: sex, age, concurrent medications, disease duration, smoking history, and intestinal disease location. Response was assessed by a face-to-face interview which was held 4 weeks after the third infusion.
Fistulas were classified into the following groups: enterocutaneous, perianal and internal, rectovaginal, and enterovesical fistulas. Patients receiving azathioprine/6-mercaptopurine were started on immunosuppressive therapy more than 6 months before the first infliximab infusion. Smokers were defined as subjects smoking a minimum of 5 cigarettes per day. Non-smokers were defined as subjects who had never smoked or subjects who had quit smoking at least 6 months before the first infusion.
Classification of response. Complete response was defined as the complete cessation of drainage from all fistulas despite gentle finger compression. Partial response was defined as at least 50% reduction from baseline in the number of fistulas or drainage for at least 4 consecut-ive weeks after the discontinuation of drug infusions. For patients with rectovaginal fistulas, response was defined as closure documented by physical examination.
Statistical analysis. For quantitative variables, mean and standard deviation were calculated. For qualitative variables, percentage and 95% confidence interval were provided. Comparisons between independent proportions Were carried out by Chi square test. Quantitative variables were compared using Student's t-test. A multiple logistic regression analysis was performed to study the association between the efficacy of infliximab (expressed in two different ways: complete response vs partial response or no response, and complete or partial response vs no response) and a number of variables: age (years), gender (male/female), smoking (smokers/non-smokers), duration of fistulizing disease (years), location of fistulas (enterocutaneous, perianal, and internal fistulas), spontaneous/postoperative nature, and concomitant immunosuppressive therapy. We used a backward modelling strategy. Log-likelihood ratio was the statistic used for model comparison.
Demographics. One hundred and eight patients were enrolled (mean age 38 yr, 53% men, 50% smokers). The mean duration of disease was 9 yr, and the mean duration of fistulizing disease was 5.4 yr. The disease was inflammatory plus fistulizing in 18%, and only fistulizing in 82% of the cases. The disease location was ileal in 31%, colonic in 18% and ileocolonic in 51% of the cases. The percentages of patients receiving concurrent therapy with other drugs were: azathioprine/6-mercaptopurine (68%), corticosteroids (55%), 5-aminosalicylates (75%), metronidazole (67%), and ciprofloxacin (32%). The number of fistulas in each patient ranged from 1 to 6 (mean 1.8). The number of fistulas by location was: 24 enterocutaneous, 59 perianal, and 12 internal (rectovaginal or enterovesical) fistulas.
Response. One hundred and five patients were finally evaluated for the study, 3 patients (2.7%) being excluded for not undergoing post-treatment check-up. After the third infusion of infliximab, 87 patients (82%) were responders: the response was partial in 26% and complete in 57% of the cases. Response rates (partial/complete, %) by location of fistulas were: enterocutaneous (25-68%), perianal (35-60%), rectovaginal (36-64%) and enterovesical (20-40%).
The characteristics of studied variables in CD patients with and without response to infliximab are shown in table I. After adjusting for age at infusion, disease duration, and sex, the logistic regression analysis showed that the variables studied (smoking, duration of fistulizing disease, fistula location, spontaneous/surgical nature, and concomitant immunosuppressive therapy) did not affect the rate of response.
Adverse effects were reported in 22 patients (21%): flu-like symptoms (3 patients), pruritus (2), headache (1), nausea (4), vomiting (2), hypotension (3), pneumonia (2), fever (1), thrombocytopenia (1), hyperbilirubinemia (1), anaphylactic reaction (2), and tuberculosis (1). Adverse effects (%) depending on the dose of infliximab infusion were: first, 5.6%, second, 7.4%, and third infusion, 11.1%.
The present study is a large trial on demographic and clinical parameters influencing short-term response to infliximab infusions in fistulizing CD. Infliximab was an effective treatment for fistulizing CD, and adverse effects were relatively infrequent and mild in most cases. After the third infusion of infliximab, the response was partial in 26% and complete in 57% of the cases. These results are better than those reported in other large trials (3-5,7,9) and similar to the data reported by Parsi et al (8), Hommes et al (10) or Arnott et al (11). The reason for this higher response rate could be related to differences in the definition of partial response, because complete response rate was similar in our study and in aforementioned studies.
None of the variables studied (i.e., age, gender, smoking, duration of fistulizing disease, fistula location, or spontaneous/surgical nature) was predictive of response in our study. One randomized trial and several retrospective studies have failed to find a significant association between each of these variables and initial response to infliximab (2,3,5,7-9). Vermiere et al (7) reported that young age favoured response, while Parsi et al (8) found that smoking was associated with a shorter duration of response.
The concurrent administration of an immunomodulator has showed no short-term advantage in fistulizing CD (2,3,7,8). We also failed to find a significant association between the concomitant administration of an immunomodulator and response to infliximab. In a "retreatment" study, however, the addition of an immunomodulator was associated with a prolonged benefit in patients treated with infliximab (12,13). Furthermore, immunogenicity and the formation of antinuclear antibodies (ANA) decreased with infliximab in combination with azathioprine, 6 mercaptopurine or methotrexate. Moreover, combination therapy with infliximab plus methotrexate in patients with rheumatoid arthritis yielded superior clinical outcomes, and resulted in a lower incidence of HACA compared to infliximab monotherapy (14).
No deaths occurred among the 108 patients included in our study. Although adverse effects were reported in 22 patients, almost all of these events were mild in severity and responded to appropriate therapy. The most serious adverse events were two pneumonias and one reactivation of pulmonary tuberculosis; none of them led to long term sequelae, and they were medically manageable.
In conclusion, infliximab was an effective treatment for fistulizing CD. Adverse effects were relatively infrequent and mild in most cases. In the short-term, none of the variables studied (i.e., age, gender, smoking, duration of fistulizing disease, fistula location, or spontaneous/surgical nature) was predictive of response, but further studies are required to evaluate long-term response to the concomitant administration of an immunomodulator and infliximab.
1. Kornbluth A. Infliximab approved for use in Crohn's disease: a report on the FDA GI Advisory Committee Conference. Inflamm Bowel Dis 1998; 4: 328-9. [ Links ]
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. N Engl J Med 1997; 337: 1029-35. [ Links ]
3. Present DH, Rutgeerts PJ, Targan SR, et al. Infliximab for the treatment of fistulas with Crohn's disease. N Engl J Med 1999; 340: 1398-405. [ Links ]
4. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn's disease first anniversary clinical experience. Am J Gastroenterol 2000; 95: 3469-77. [ Links ]
5. Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with infliximab therapy in 100 patients with Crohn's disease. Am J Gastroenterol. 200; 95: 3490-7. [ Links ]
6. Hanauer SB, Feagan BG, Linchtestein GR, et al. Infliximab for Crohn's disease. The ACCENT I randomized trial. Lancet 2002; 359: 1541-9. [ Links ]
7. Vermeire S, Louis E, Arbonez A, et al. Demographic and clinical parameters influencing the sort-term outcome of anti-tumoral necrosis factor (Infliximab) treatment in Crohn's disease. Am J Gastroenterol 2002; 97: 2357-63. [ Links ]
8. Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology 2002; 123: 707-13. [ Links ]
9. Sand B, Van Deventer S, Bemsteins S, et al. Long-term treatment of fistulizing Crohn's disease: response to infliximab in the Accent II trial through 54 weeks (abstract). Gastroenterology 2002; 122: A81. [ Links ]
10. Homes DW, van de Heisgteeg BH, van der Spek M, Bartelman JFWM, van Deventer SJH. Infliximab treatment for Crohn's disease: One year experience in a Dutch Academic Hospital. Inflamm Bowel Dis 2002; 8: 81-6. [ Links ]
11. Arnott IDR, MacNeill 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: 1451-7. [ Links ]
12. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117: 761-9. [ Links ]
13. Baerts F, Noman M, Vermiere S, et al. Influence of immunogenicity on the log-term efficacy of infliximab in Crohn's disease. N Eng J Med 2003; 348: 601-8. [ Links ]
14. Lipsky PE, Van der Heijde DMFM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594-602. [ Links ]