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.

 

ABSTRACT

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.

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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.

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Recibido: 17-12-03.
Aceptado: 23-12-03.

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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

 

INTRODUCTION

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.

METHODS

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.

RESULTS

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%.

DISCUSSION

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.

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