Treatment of Ulcerative Colitis
Infliximab was the first anti-TNF-[alpha] antibody that was approved by the US Food and Drug Administration for the treatment of moderate-to-severe ulcerative colitis to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa and to eliminate the use of corticosteroids in patients who did not have adequate response or who were intolerant or have medical contraindications to therapy with corticosteroids or immune modulators.
Induction therapy with infliximab consists of three intravenous infusions at the dose of 5 mg/kg over 2 h at week 0, 2 and 6. Prior to initiation of treatment with infliximab, administration of corticosteroids or AZA/6-mercaptopurine may be considered in order to reduce the formation of antibodies to infliximab (ATIs). Successful induction therapy is followed by maintenance treatment every 8 weeks. In case of no response to induction therapy with infliximab, further maintenance treatment with infliximab is not recommended.
According to Cochrane meta-analysis of two landmark randomized placebo-controlled Active Ulcerative Colitis Trials (ACT 1 and ACT 2) with a total of 728 patients, treatment with infliximab was three-fold more efficacious than placebo in inducing clinical remission, nearly two-fold more efficacious in inducing clinical response or endoscopic remission at week 8 in patients presenting with moderate-to-severe ulcerative colitis refractory to conventional treatment with corticosteroids and/or immune modulators (Table 2).
Overall, the ACT 1 and ACT 2 trials observed a comparable proportion of adverse events in both treatment arms. However, the proportion of patients with infections that needed antimicrobial treatment was significantly higher in infliximab-treated patients in ACT 1 (30 vs. 21%, P = 0.001). However, significantly more patients receiving placebo experienced adverse events causing discontinuation of studied drug (10 vs. 3%, P = 0.01) or serious adverse events (10 vs. 19.5%, P = 0.01) in ACT 2. Both ACT 1 and ACT 2 showed statistically significantly higher rates of antinuclear antibodies and antibodies to double-stranded DNA in patients treated with infliximab than placebo. ATIs were present in 3–10% of patients treated with infliximab. Acute infusion reactions were observed in 8–12% of all patients. The development of tuberculosis (n = 1) and fatal pulmonary histoplasmosis (n = 1) occurred in infliximab recipients. Prior to initiation of infliximab therapy, patients should be screened for latent tuberculosis with a subcutaneous tuberculin test (ppd).
Data from a recent systematic review of literature indicated that men younger than 35 years treated with combination therapy of infliximab and AZA/6-mercaptopurine are at the risk for developing hepatosplenic T-cell lymphoma. However, the actual risk for this lethal diagnosis is low and has been estimated to occur with an absolute risk of 36 in 1.6 million or 1 : 44 444 patients. It is perceived that the agent that is responsible for the lymphoma is the AZA, as there have been no patients who had HSTCL develop with IBD who had only been treated with anti-TNF therapy. All patients received past or current AZA or 6-mercaptopurine. Nevertheless, combination treatment with AZA and infliximab should be initiated in young men when appropriate.
ADA, a fully human monoclonal anti-TNF-[alpha] antibody has been recently approved by the US Food and Drug Administration as an induction agent and also as an agent effective for maintenance of clinical remission in adult patients with moderate-to-severe ulcerative colitis who did not demonstrate adequate response to corticosteroids, AZA/6-mercaptopurine (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321650.htm. Accessed date Aug 22, 2013). There is no primary trial that has established efficacy of this agent in treating patients with ulcerative colitis who lost response or were intolerant to infliximab. However, many patients who entered clinical trials evaluating the efficacy of ADA in ulcerative colitis were individuals who lost response or were intolerant to infliximab and were effectively treated with ADA.
The following treatment regimen with ADA administered subcutaneously is currently recommended. The initial dose of ADA is 160 mg given on day 1 as either four injections of 40 mg each in 1 day or two 40 mg injections per day given over 2 consecutive days. Two weeks later, ADA should be given at the single dose of 80 mg. After another 2 weeks, ADA should be started at the dose of 40 mg every other week. It is recommended to continue ADA only in patients who have demonstrated evidence of clinical remission after 8 weeks from the initial dose. Treatment with 5-ASA, corticosteroids and AZA/6-mercaptopurine may be continued during treatment with ADA.
The efficacy and safety of ADA as induction and maintenance treatment in patients with moderate-to-severe ulcerative colitis were determined in two multicenter, double-blind, RCTs named Ulcerative colitis Long-term Remission and maintenance with Adalimumab 1 and 2 (ULTRA 1 and ULTRA 2) with open-label extension of ULTRA 1 (Table 2).
An analysis of the benefit-to-risk balance of ADA suggested that patients treated with ADA had a statistically significantly two-fold greater likelihood of achieving clinical remission or clinical response at week 8 and week 52 without any serious adverse events or serious infections when compared with placebo. It was also suggested that early response to ADA was predictive of a positive outcome after 1 year of treatment with ADA.
Golimumab, a fully human monoclonal anti-TNF-[alpha] antibody, has been recently approved by the US Food and Drug Administration for inducing and maintaining clinical response and clinical remission and inducing mucosal healing in patients with moderate-to-severe ulcerative colitis who have had an inadequate response to prior treatment, who do not tolerate prior treatment or who require continuous treatment with corticosteroids (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352383.htm Accessed date Sep 6, 2013).
Golimumab is initially administered subcutaneously at the dose of 200 mg at week 0 followed by 100 mg at week 2 and after that every 4 weeks.
There has been one randomized placebo-controlled trial [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous (PURSUIT-SC)] that assessed induction therapy with subcutaneous golimumab in anti-TNF-[alpha]-naïve patients with moderate-to-severe ulcerative colitis (Mayo score 6–12 points with an endoscopic subscore >=2 points) not responding to conventional therapy with oral mesalamine, oral corticosteroids, AZA/6-mercaptopurine or unable to taper corticosteroids without recurrence of ulcerative colitis activity (Table 2). The subsequent PURSUIT-M randomized placebo controlled trial assessed the efficacy and safety of golimumab in maintaining clinical response in patients who responded to induction treatment with golimumab in the preceding PURSUIT-SC trial (Table 2). Golimumab was shown to be more efficacious than placebo in inducing clinical response, remission and mucosal healing and increasing quality of life.
Antitumor Necrosis Factor Alpha Antibodies
Infliximab
Infliximab was the first anti-TNF-[alpha] antibody that was approved by the US Food and Drug Administration for the treatment of moderate-to-severe ulcerative colitis to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa and to eliminate the use of corticosteroids in patients who did not have adequate response or who were intolerant or have medical contraindications to therapy with corticosteroids or immune modulators.
Induction therapy with infliximab consists of three intravenous infusions at the dose of 5 mg/kg over 2 h at week 0, 2 and 6. Prior to initiation of treatment with infliximab, administration of corticosteroids or AZA/6-mercaptopurine may be considered in order to reduce the formation of antibodies to infliximab (ATIs). Successful induction therapy is followed by maintenance treatment every 8 weeks. In case of no response to induction therapy with infliximab, further maintenance treatment with infliximab is not recommended.
According to Cochrane meta-analysis of two landmark randomized placebo-controlled Active Ulcerative Colitis Trials (ACT 1 and ACT 2) with a total of 728 patients, treatment with infliximab was three-fold more efficacious than placebo in inducing clinical remission, nearly two-fold more efficacious in inducing clinical response or endoscopic remission at week 8 in patients presenting with moderate-to-severe ulcerative colitis refractory to conventional treatment with corticosteroids and/or immune modulators (Table 2).
Overall, the ACT 1 and ACT 2 trials observed a comparable proportion of adverse events in both treatment arms. However, the proportion of patients with infections that needed antimicrobial treatment was significantly higher in infliximab-treated patients in ACT 1 (30 vs. 21%, P = 0.001). However, significantly more patients receiving placebo experienced adverse events causing discontinuation of studied drug (10 vs. 3%, P = 0.01) or serious adverse events (10 vs. 19.5%, P = 0.01) in ACT 2. Both ACT 1 and ACT 2 showed statistically significantly higher rates of antinuclear antibodies and antibodies to double-stranded DNA in patients treated with infliximab than placebo. ATIs were present in 3–10% of patients treated with infliximab. Acute infusion reactions were observed in 8–12% of all patients. The development of tuberculosis (n = 1) and fatal pulmonary histoplasmosis (n = 1) occurred in infliximab recipients. Prior to initiation of infliximab therapy, patients should be screened for latent tuberculosis with a subcutaneous tuberculin test (ppd).
Data from a recent systematic review of literature indicated that men younger than 35 years treated with combination therapy of infliximab and AZA/6-mercaptopurine are at the risk for developing hepatosplenic T-cell lymphoma. However, the actual risk for this lethal diagnosis is low and has been estimated to occur with an absolute risk of 36 in 1.6 million or 1 : 44 444 patients. It is perceived that the agent that is responsible for the lymphoma is the AZA, as there have been no patients who had HSTCL develop with IBD who had only been treated with anti-TNF therapy. All patients received past or current AZA or 6-mercaptopurine. Nevertheless, combination treatment with AZA and infliximab should be initiated in young men when appropriate.
Adalimumab
ADA, a fully human monoclonal anti-TNF-[alpha] antibody has been recently approved by the US Food and Drug Administration as an induction agent and also as an agent effective for maintenance of clinical remission in adult patients with moderate-to-severe ulcerative colitis who did not demonstrate adequate response to corticosteroids, AZA/6-mercaptopurine (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321650.htm. Accessed date Aug 22, 2013). There is no primary trial that has established efficacy of this agent in treating patients with ulcerative colitis who lost response or were intolerant to infliximab. However, many patients who entered clinical trials evaluating the efficacy of ADA in ulcerative colitis were individuals who lost response or were intolerant to infliximab and were effectively treated with ADA.
The following treatment regimen with ADA administered subcutaneously is currently recommended. The initial dose of ADA is 160 mg given on day 1 as either four injections of 40 mg each in 1 day or two 40 mg injections per day given over 2 consecutive days. Two weeks later, ADA should be given at the single dose of 80 mg. After another 2 weeks, ADA should be started at the dose of 40 mg every other week. It is recommended to continue ADA only in patients who have demonstrated evidence of clinical remission after 8 weeks from the initial dose. Treatment with 5-ASA, corticosteroids and AZA/6-mercaptopurine may be continued during treatment with ADA.
The efficacy and safety of ADA as induction and maintenance treatment in patients with moderate-to-severe ulcerative colitis were determined in two multicenter, double-blind, RCTs named Ulcerative colitis Long-term Remission and maintenance with Adalimumab 1 and 2 (ULTRA 1 and ULTRA 2) with open-label extension of ULTRA 1 (Table 2).
An analysis of the benefit-to-risk balance of ADA suggested that patients treated with ADA had a statistically significantly two-fold greater likelihood of achieving clinical remission or clinical response at week 8 and week 52 without any serious adverse events or serious infections when compared with placebo. It was also suggested that early response to ADA was predictive of a positive outcome after 1 year of treatment with ADA.
Golimumab
Golimumab, a fully human monoclonal anti-TNF-[alpha] antibody, has been recently approved by the US Food and Drug Administration for inducing and maintaining clinical response and clinical remission and inducing mucosal healing in patients with moderate-to-severe ulcerative colitis who have had an inadequate response to prior treatment, who do not tolerate prior treatment or who require continuous treatment with corticosteroids (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352383.htm Accessed date Sep 6, 2013).
Golimumab is initially administered subcutaneously at the dose of 200 mg at week 0 followed by 100 mg at week 2 and after that every 4 weeks.
There has been one randomized placebo-controlled trial [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous (PURSUIT-SC)] that assessed induction therapy with subcutaneous golimumab in anti-TNF-[alpha]-naïve patients with moderate-to-severe ulcerative colitis (Mayo score 6–12 points with an endoscopic subscore >=2 points) not responding to conventional therapy with oral mesalamine, oral corticosteroids, AZA/6-mercaptopurine or unable to taper corticosteroids without recurrence of ulcerative colitis activity (Table 2). The subsequent PURSUIT-M randomized placebo controlled trial assessed the efficacy and safety of golimumab in maintaining clinical response in patients who responded to induction treatment with golimumab in the preceding PURSUIT-SC trial (Table 2). Golimumab was shown to be more efficacious than placebo in inducing clinical response, remission and mucosal healing and increasing quality of life.
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