Original Paper Received: March 25, 2013 Accepted: September 9, 2013 Published online: November 22, 2013
Digestion 2013;88:222–228 DOI: 10.1159/000355529
Clinical Efficacy of Infliximab in Moderate to Severe Ulcerative Colitis in a Latin American Referral Population Fabian Juliao a, c Juan Marquez b Natalia Aristizabal a Carlos Yepes a, c Julio Zuleta a Javier P. Gisbert d
c
Division of Gastroenterology, Pablo Tobón Uribe Hospital, b Division of Coloproctology, Las Americas Clinic, and University of Antioquia, Medellín, Colombia; d La Princesa Hospital, IP and CIBEREHD, Madrid, Spain
Key Words Ulcerative colitis · Infliximab · Tumor necrosis factor α · Anti-tumor necrosis factor α
Abstract Background: Previous research has shown that infliximab (IFX) is effective in the management of moderate to severe active ulcerative colitis (UC). Latin American studies are lacking. Aim: To evaluate the efficacy of IFX treatment (including corticosteroid withdrawal, complete mucosal healing, colectomy and hospitalization rates) in patients with moderate to severe UC. Methods: A retrospective and descriptive study was conducted on patients with UC in Medellín (Colombia). We included patients steroid dependent or refractory to conventional treatment. Results: Between October 2005 and July 2011, 28 patients with moderate to severe UC received IFX infusions; the median of the follow-up was 27.4 months (range: 1–69 months). Twenty-four patients (86%) had a short-term primary response, whilst 19 (68%) achieved initial clinical remission. After 1 year, 17 (71%) out of the 24 patients who had an initial response were also showing a sustained response, and 10 (42%) remained in clinical remission. At 6 months, complete mucosal healing was observed in 29% of patients and endoscopic improvement in 57%. Conclusions:
© 2013 S. Karger AG, Basel 0012–2823/13/0884–0222$38.00/0 E-Mail [email protected] www.karger.com/dig
This is the first study to evaluate the IFX use in patients with moderate to severe active UC in a Latin American population. We found that IFX therapy is effective for inducing clinical remission, and that most patients who had an initial response showed a long-term sustained response. © 2013 S. Karger AG, Basel
Introduction
Ulcerative colitis (UC) is a chronic inflammatory disease with a multifactorial etiology. UC is characterized by erosions and/or ulcerations of the colonic mucosa, rectal bleeding and diarrhea. A recent Colombian study [1] conducted on 202 patients with diagnoses of inflammatory bowel disease found that there was a higher proportion of patients with UC (80.7%) compared to those with Crohn’s disease (15.8%; 5:1). This ratio is different from what was observed in studies from developed countries, where the proportion of the two diseases is very similar. The pharmacological management of patients with UC is based mainly on the use of medications such as 5-aminosalicylic acid, steroids and immunosuppressant agents such as thiopurines. However, steroid dependence is an important clinical problem (22% after 1 year) [2], Fabián Juliao Department of Gastroenterology, Pablo Tobón Uribe Hospital Calle 78 B, No. 69–240 Medellín (Colombia) E-Mail fabianjuliao @ hotmail.com
Downloaded by: University of Washington 128.95.104.66 - 10/28/2014 3:15:47 AM
a
Materials and Methods
treatment every 8 weeks. All patients were asked to undergo a chest radiograph and a tuberculin skin test before initiating therapy with TNF-α blockers. Patients with latent tuberculosis infection were evaluated by an infectiologist for further evaluation and management, according to international recommendations [12]. The endoscopic severity and extent of the UC were determined based on the last colonoscopy before the beginning of the treatment with IFX. Likewise, a colonoscopy was performed on all patients approximately 6 months after the start of the IFX treatment in order to assess endoscopic response. Outcome Measures and Definitions The following outcomes were measured: (1) clinical response and clinical remission after 12 weeks, 6 months and 1 year; (2) primary nonresponse and loss of response to IFX; (3) need for IFX optimization; (4) complete mucosal healing at month 6; (5) frequency of hospitalization and colectomy for intractable disease during treatment. The Mayo Clinic score [13] was used, and it includes 4 items: number of stools, presence of bleeding, physician global evaluation and endoscopic severity. Clinical response was defined as a decrease from baseline in the Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Clinical remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. The modified Mayo Clinic score was used without including the endoscopic score, to measure short-term clinical and sustained response after the 1-year follow-up period. Primary nonresponse to IFX was defined as a lack of clinical response before week 12 of therapy after the first IFX infusion, resulting in treatment discontinuation. Complete mucosal healing was defined as the absence of mucosal ulceration (subscore for endoscopy of 0) at month 6 in patients who had confirmed mucosal ulceration at baseline. Patients with a reduced nonzero endoscopic score were included in the partial response category. IFX optimization was defined as all therapeutic options required for maintaining clinical benefit as judged by the physician. Optimization included any shortening of the interval between IFX infusions (up to 4-week interval) and/or an increasing IFX dose from 5 to 10 mg/kg. Failure of infliximab treatment was defined as one of the three following criteria: IFX withdrawal due to intolerance, loss of clinical response or switching to another anti-TNF-α. Sustained clinical response was defined as persistent clinical improvement during follow-up without the need for new courses of corticosteroids or any other systemic drug (cyclosporine, azathioprine, methotrexate, investigational drugs), and was only assessed in patients who achieved an initial clinical response. All hospitalizations and colectomies for intractable disease were registered. In addition, patients were considered to be steroid dependent when it was not possible to stop this medication or when patients had relapses within 3 months of steroid suspension [14].
Study Design The Pablo Tobón Uribe Hospital and the Americas Clinic are located in Medellin (Colombia). These are reference centers for difficult-to-treat diseases such as inflammatory bowel disease. In 2001 the inflammatory bowel disease clinic was established at the Pablo Tobón Uribe Hospital. A retrospective descriptive study was conducted between October 2005 and July 2011. The clinical records of all the UC patients who had been administered at least 1 infusion of IFX were reviewed. The diagnosis of UC was made according to the criteria of the European Crohn’s and Colitis Organization [10], and patients were classified based on extent and severity according to the Montreal Classification [11]. We included patients with moderate to severe UC who were steroid dependent or refractory to conventional treatment. Patients with acute severe UC refractory to intravenous steroids were excluded. IFX was administered at a dose of 5 mg/kg by means of a continuous infusion for 2 h as an induction protocol at 0, 2, and 6 weeks. Patients who showed a primary response continued to receive maintenance
Statistical Analysis We carried out a descriptive analysis of the frequencies of the categorical clinical variables. Similarly, the mean and median for the continuous variables were calculated with their corresponding variability measures based on whether the distribution was or was not normal. A bivariate analysis was carried out using either the χ2 test or Fisher’s exact test if necessary to cross the categorical vari-
Infliximab in Ulcerative Colitis in Latin America
Digestion 2013;88:222–228 DOI: 10.1159/000355529
223
Downloaded by: University of Washington 128.95.104.66 - 10/28/2014 3:15:47 AM
and the probability of colectomy after 5 years is 9% for patients with proctitis and 35% when the involvement is extensive [3]. On the other hand, the disease’s risk of recurrence in the form of ileal pouch inflammation (pouchitis) in UC patients who have undergone colectomy is 15% after 1 year and 45% after a 10-year follow-up [4]. The tumor necrosis factor α (TNF-α) is a proinflammatory cytokine playing a key role in the Th1 cellular response, which is predominant in patients with Crohn’s disease. However, it has been found that during acute episodes, UC patients have high serum, stool, and tissue levels of TNF-α, which is similar to what happens in Crohn’s disease [5, 6]. Infliximab (IFX) is an IgG1-type chimeric monoclonal antibody directed against the TNF-α. The ACT 1 and ACT 2 trials on patients with moderate to severe UC that was refractory to conventional treatment proved the efficacy of IFX both for improving the clinical response and for reducing rates of colectomy and hospitalization [7, 8]. A systematic review of controlled doubleblind clinical studies found long-term response and remission rates (average follow-up time 8.9 months) of 53 and 39%, respectively. In patients with UC and receiving IFX, the number needed to treat was 3–5, and the number needed to harm was 14 [9]. The aim of this study was to assess the short- and long-term response to IFX in moderate to severe UC patients from our population, who were steroid dependent or refractory to conventional treatment. Additionally, this study aimed at determining the need for IFX optimization, steroid withdrawal, complete mucosal healing, colectomy, and hospitalization rates.
Ethical Considerations The protocol of this study was approved in advance by the Ethical Review Board at Pablo Tobón Uribe Hospital. Confidentiality was observed, and it was not necessary for patients to sign an informed consent form in order to participate in the study as there was no additional patient involvement beyond the accessing of their clinical records. Moreover, because information was gathered retrospectively from clinical records, this study had the ‘research without risk’ status in accordance with Article 11, Resolution 8430 of 1993, issued by the Colombian Health Ministry.
Results
Thirty patients with UC received infusions of IFX between October 2005 and July 2011. The average age when starting the biological treatment was 35 years (from 2 to 66 years). The median duration of the disease from diagnosis to the start of the biological therapy was 3.7 years (interval: from
Digestion 2013;88:222–228 DOI: 10.1159/000355529
Clinical Efficacy of Infliximab in Moderate to Severe Ulcerative Colitis in a Latin American Referral Population Fabian Juliao a, c Juan Marquez b Natalia Aristizabal a Carlos Yepes a, c Julio Zuleta a Javier P. Gisbert d
c
Division of Gastroenterology, Pablo Tobón Uribe Hospital, b Division of Coloproctology, Las Americas Clinic, and University of Antioquia, Medellín, Colombia; d La Princesa Hospital, IP and CIBEREHD, Madrid, Spain
Key Words Ulcerative colitis · Infliximab · Tumor necrosis factor α · Anti-tumor necrosis factor α
Abstract Background: Previous research has shown that infliximab (IFX) is effective in the management of moderate to severe active ulcerative colitis (UC). Latin American studies are lacking. Aim: To evaluate the efficacy of IFX treatment (including corticosteroid withdrawal, complete mucosal healing, colectomy and hospitalization rates) in patients with moderate to severe UC. Methods: A retrospective and descriptive study was conducted on patients with UC in Medellín (Colombia). We included patients steroid dependent or refractory to conventional treatment. Results: Between October 2005 and July 2011, 28 patients with moderate to severe UC received IFX infusions; the median of the follow-up was 27.4 months (range: 1–69 months). Twenty-four patients (86%) had a short-term primary response, whilst 19 (68%) achieved initial clinical remission. After 1 year, 17 (71%) out of the 24 patients who had an initial response were also showing a sustained response, and 10 (42%) remained in clinical remission. At 6 months, complete mucosal healing was observed in 29% of patients and endoscopic improvement in 57%. Conclusions:
© 2013 S. Karger AG, Basel 0012–2823/13/0884–0222$38.00/0 E-Mail [email protected] www.karger.com/dig
This is the first study to evaluate the IFX use in patients with moderate to severe active UC in a Latin American population. We found that IFX therapy is effective for inducing clinical remission, and that most patients who had an initial response showed a long-term sustained response. © 2013 S. Karger AG, Basel
Introduction
Ulcerative colitis (UC) is a chronic inflammatory disease with a multifactorial etiology. UC is characterized by erosions and/or ulcerations of the colonic mucosa, rectal bleeding and diarrhea. A recent Colombian study [1] conducted on 202 patients with diagnoses of inflammatory bowel disease found that there was a higher proportion of patients with UC (80.7%) compared to those with Crohn’s disease (15.8%; 5:1). This ratio is different from what was observed in studies from developed countries, where the proportion of the two diseases is very similar. The pharmacological management of patients with UC is based mainly on the use of medications such as 5-aminosalicylic acid, steroids and immunosuppressant agents such as thiopurines. However, steroid dependence is an important clinical problem (22% after 1 year) [2], Fabián Juliao Department of Gastroenterology, Pablo Tobón Uribe Hospital Calle 78 B, No. 69–240 Medellín (Colombia) E-Mail fabianjuliao @ hotmail.com
Downloaded by: University of Washington 128.95.104.66 - 10/28/2014 3:15:47 AM
a
Materials and Methods
treatment every 8 weeks. All patients were asked to undergo a chest radiograph and a tuberculin skin test before initiating therapy with TNF-α blockers. Patients with latent tuberculosis infection were evaluated by an infectiologist for further evaluation and management, according to international recommendations [12]. The endoscopic severity and extent of the UC were determined based on the last colonoscopy before the beginning of the treatment with IFX. Likewise, a colonoscopy was performed on all patients approximately 6 months after the start of the IFX treatment in order to assess endoscopic response. Outcome Measures and Definitions The following outcomes were measured: (1) clinical response and clinical remission after 12 weeks, 6 months and 1 year; (2) primary nonresponse and loss of response to IFX; (3) need for IFX optimization; (4) complete mucosal healing at month 6; (5) frequency of hospitalization and colectomy for intractable disease during treatment. The Mayo Clinic score [13] was used, and it includes 4 items: number of stools, presence of bleeding, physician global evaluation and endoscopic severity. Clinical response was defined as a decrease from baseline in the Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Clinical remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. The modified Mayo Clinic score was used without including the endoscopic score, to measure short-term clinical and sustained response after the 1-year follow-up period. Primary nonresponse to IFX was defined as a lack of clinical response before week 12 of therapy after the first IFX infusion, resulting in treatment discontinuation. Complete mucosal healing was defined as the absence of mucosal ulceration (subscore for endoscopy of 0) at month 6 in patients who had confirmed mucosal ulceration at baseline. Patients with a reduced nonzero endoscopic score were included in the partial response category. IFX optimization was defined as all therapeutic options required for maintaining clinical benefit as judged by the physician. Optimization included any shortening of the interval between IFX infusions (up to 4-week interval) and/or an increasing IFX dose from 5 to 10 mg/kg. Failure of infliximab treatment was defined as one of the three following criteria: IFX withdrawal due to intolerance, loss of clinical response or switching to another anti-TNF-α. Sustained clinical response was defined as persistent clinical improvement during follow-up without the need for new courses of corticosteroids or any other systemic drug (cyclosporine, azathioprine, methotrexate, investigational drugs), and was only assessed in patients who achieved an initial clinical response. All hospitalizations and colectomies for intractable disease were registered. In addition, patients were considered to be steroid dependent when it was not possible to stop this medication or when patients had relapses within 3 months of steroid suspension [14].
Study Design The Pablo Tobón Uribe Hospital and the Americas Clinic are located in Medellin (Colombia). These are reference centers for difficult-to-treat diseases such as inflammatory bowel disease. In 2001 the inflammatory bowel disease clinic was established at the Pablo Tobón Uribe Hospital. A retrospective descriptive study was conducted between October 2005 and July 2011. The clinical records of all the UC patients who had been administered at least 1 infusion of IFX were reviewed. The diagnosis of UC was made according to the criteria of the European Crohn’s and Colitis Organization [10], and patients were classified based on extent and severity according to the Montreal Classification [11]. We included patients with moderate to severe UC who were steroid dependent or refractory to conventional treatment. Patients with acute severe UC refractory to intravenous steroids were excluded. IFX was administered at a dose of 5 mg/kg by means of a continuous infusion for 2 h as an induction protocol at 0, 2, and 6 weeks. Patients who showed a primary response continued to receive maintenance
Statistical Analysis We carried out a descriptive analysis of the frequencies of the categorical clinical variables. Similarly, the mean and median for the continuous variables were calculated with their corresponding variability measures based on whether the distribution was or was not normal. A bivariate analysis was carried out using either the χ2 test or Fisher’s exact test if necessary to cross the categorical vari-
Infliximab in Ulcerative Colitis in Latin America
Digestion 2013;88:222–228 DOI: 10.1159/000355529
223
Downloaded by: University of Washington 128.95.104.66 - 10/28/2014 3:15:47 AM
and the probability of colectomy after 5 years is 9% for patients with proctitis and 35% when the involvement is extensive [3]. On the other hand, the disease’s risk of recurrence in the form of ileal pouch inflammation (pouchitis) in UC patients who have undergone colectomy is 15% after 1 year and 45% after a 10-year follow-up [4]. The tumor necrosis factor α (TNF-α) is a proinflammatory cytokine playing a key role in the Th1 cellular response, which is predominant in patients with Crohn’s disease. However, it has been found that during acute episodes, UC patients have high serum, stool, and tissue levels of TNF-α, which is similar to what happens in Crohn’s disease [5, 6]. Infliximab (IFX) is an IgG1-type chimeric monoclonal antibody directed against the TNF-α. The ACT 1 and ACT 2 trials on patients with moderate to severe UC that was refractory to conventional treatment proved the efficacy of IFX both for improving the clinical response and for reducing rates of colectomy and hospitalization [7, 8]. A systematic review of controlled doubleblind clinical studies found long-term response and remission rates (average follow-up time 8.9 months) of 53 and 39%, respectively. In patients with UC and receiving IFX, the number needed to treat was 3–5, and the number needed to harm was 14 [9]. The aim of this study was to assess the short- and long-term response to IFX in moderate to severe UC patients from our population, who were steroid dependent or refractory to conventional treatment. Additionally, this study aimed at determining the need for IFX optimization, steroid withdrawal, complete mucosal healing, colectomy, and hospitalization rates.
Ethical Considerations The protocol of this study was approved in advance by the Ethical Review Board at Pablo Tobón Uribe Hospital. Confidentiality was observed, and it was not necessary for patients to sign an informed consent form in order to participate in the study as there was no additional patient involvement beyond the accessing of their clinical records. Moreover, because information was gathered retrospectively from clinical records, this study had the ‘research without risk’ status in accordance with Article 11, Resolution 8430 of 1993, issued by the Colombian Health Ministry.
Results
Thirty patients with UC received infusions of IFX between October 2005 and July 2011. The average age when starting the biological treatment was 35 years (from 2 to 66 years). The median duration of the disease from diagnosis to the start of the biological therapy was 3.7 years (interval: from
