Active Ulcerative Colitis Trials Research Articles

Gender-Based Differences in Response to Tumor Necrosis Factor Inhibitor Therapies for Ulcerative Colitis: Individual Participant Data Meta-Analyses of Clinical Trials.

Gender-based differences are reported in inflammatory bowel diseases (IBD) pathogenesis, but their impacts on IBD outcomes are not well known. We determined gender-based differences in response to treatment with tumor necrosis factor inhibitor (TNFi) therapies in individuals with ulcerative colitis (UC). We used the Yale University Open Data Access (YODA) platform to abstract individual participant data from randomized clinical trials to study infliximab and golimumab as induction and maintenance therapies in moderately to severely active UC. Using multivariable logistic regression, we examined associations between gender and the endpoints of clinical remission, mucosal healing, and clinical response for each study individually and in a meta-analysis. Of 1639 patients included in induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous [PURSUIT-SC], active ulcerative colitis trials [ACT] 1 and 2) and 1280 patients included in maintenance trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Maintenance [PURSUIT-IM], ACT 1 and 2), 696 (42.5%) and 534 (41.7%) were women, respectively. In a meta-analysis of induction trials, the adjusted odds ratios (aORs) of clinical remission (aOR, 0.55; 95% CI, 0.31-0.97), mucosal healing (aOR, 0.47; 95% CI, 0.27-0.83), and clinical response (aOR, 0.51; 95% CI, 0.29-0.90) in the treatment arm and of clinical remission in the placebo arm (aOR, 0.34; 95% CI, 0.15-0.82) were lower in men compared to women. There were no differences in outcomes by gender in the treatment and placebo arms in the meta-analysis of maintenance trials. Men are less likely to achieve clinical remission, mucosal healing, and clinical response compared to women during induction treatment with TNFi for UC, but not during the maintenance phase. Future studies delineating the mechanisms underlying these observations would be informative.

Early Symptomatic Improvement After Ustekinumab Therapy in Patients With Ulcerative Colitis: 16-Week Data From the UNIFI Trial

Rapid symptomatic relief is an important treatment goal for patients with ulcerative colitis (UC). We aimed to characterize early response with ustekinumab in patients with moderate-to-severe UC during the initial 16 weeks of treatment. We performed a post hoc analysis of data from A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis trial. Patients (N= 961) were randomized (1:1:1) to receive intravenous 130 mg ustekinumab, approximately 6 mg/kg ustekinumab, or placebo at week 0. Symptomatic remission, absolute stool number, Mayo stool frequency and rectal bleeding subscores, partial Mayo score, C-reactive protein, and fecal calprotectin were assessed in the overall population and for patients in the biologic-naïve or prior biologic failure subgroups. A significantly greater percentage of patients in the 130-mg ustekinumab (20.0%; P= .015) or approximately 6-mg/kg ustekinumab (20.2%; P= .012) groups achieved symptomatic remission at week 2 vs placebo (12.9%). Mean [SD] changes from baseline in daily stool number on day 7 were greater in the ustekinumab groups (-1.1 [2.6] in 130 mg [P= .065] and -1.2 [2.5] in ∼6 mg/kg [P= .017]) vs placebo (-0.7 [2.7]). The percentage of patients with Mayo stool frequency subscore of 1 or less and rectal bleeding subscore of 0 increased from baseline through week 16 for both ustekinumab groups. Significant improvements in partial Mayo scores were observed by week 2 in both ustekinumab groups vs placebo (P ≤ .001). Significantly more patients in the ustekinumab groups had normalized C-reactive protein levels from week 2 to week 8 vs placebo (P ≤ .05). Similar results were observed with normalized fecal calprotectin levels between week 2 and week 4 (P ≤ .05). Ustekinumab improved symptoms in patients with UC compared with placebo in as early as 7 days, indicating rapid onset of effect after induction. ClinicalTrials.gov: NCT02407236.

Development and Validation of a Clinical Decision Support Tool That Incorporates Pharmacokinetic Data to Predict Endoscopic Healing in Patients Treated With Infliximab

Infliximab is an effective treatment for moderate to severe ulcerative colitis (UC). Little is known about patient-related factors that might be used to predict endoscopic healing with infliximab therapy. We analyzed data from 484 patients included in the randomized trials of the effects of infliximab therapy for patients with UC (Active Ulcerative Colitis Trials [ACT]-1 and ACT-2). We used a 2-compartment population pharmacokinetic model to calculate baseline infliximab clearance. Two multivariable regression models were derived and validated for their ability to identify patients with endoscopic healing (Mayo endoscopic score, ≤1) at weeks 8 and 30, using only baseline variables. We developed a clinical decision support tool (CDST) and calculator to determine the probability of endoscopic healing in patients starting infliximab. Higher baseline infliximab clearance, stool frequency, and rectal bleeding scores were associated negatively with endoscopic healing at week 8. In the validation set, a CDST score of 9 points or fewer identified patients without endoscopic healing at week 8 with 82% sensitivity (95% CI, 76%-88%), whereas a CDST score of 16 points or more identified patients with endoscopic healing at week 8 with 87% specificity (95% CI, 81%-94%). Higher baseline infliximab clearance, stool frequency score, white blood cell count, and lower body weight were associated negatively with endoscopic healing at week 30. In the validation set, CDST scores of 17 points or fewer identified patients without endoscopic healing at week 30 with 90% sensitivity (95% CI, 85%-95%), whereas scores greater than 22 points identified patients with endoscopic healing at week 30 with 80% specificity (95% CI, 73%-87%). External validation models had a modest predictive value, with an area under of the curve of 0.67 (95% CI, 0.61-0.74). Patient-level probabilities of endoscopic healing at weeks 8 or 30 can be calculated online (www.premedibd.com). Using data from 2 clinical trials of patients receiving infliximab therapy for UC, we developed and validated the CDST, which uses data on infliximab clearance and baseline patient and disease measures to identify patients most likely to have endoscopic healing. This tool will facilitate therapy decision making and precision medicine.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation

Objective: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada).Methods: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs).Results: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY.Limitations: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze.Conclusion: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000–$100,000 per QALY.

Cost‐Utility Analysis of Infliximab with Standard Care versus Standard Care Alone for Induction and Maintenance Treatment of Patients with Ulcerative Colitis in Poland

To assess the cost-effectiveness of infliximab with standard care (e.g., azathioprine, prednisolone, mesalazine, and 6-mercaptopurine) versus standard care alone for induction and maintenance treatment of patients with ulcerative colitis (UC) in Poland. Cost-utility decision analytic model. A Markov model was used to estimate the expected costs and effects of infliximab/standard care and standard care alone. For each treatment option, costs and quality-adjusted life-years (QALYs) were calculated to estimate the incremental cost-utility ratio. The target population consisted of a hypothetical cohort of adult patients with moderately to severely active UC who had an inadequate response to standard treatment, including corticosteroids and 6-mercaptopurine or azathioprine, or who were intolerant to or had medical contraindications to such therapies. The analysis was performed from the perspective of the Polish public payer over a 30-year time horizon. The clinical parameters were derived mainly from the Active Ulcerative Colitis Trial (ACT) 1 and ACT 2 and from the Ulcerative Colitis Long-term Remission and Maintenance with Adalimumab (ULTRA) 2 clinical trial. Different costs and utility values were assigned to the various health states in the model; utility values were derived from a previously published study. Treatment of patients who received infliximab/standard care instead of standard care alone resulted in 0.174 additional QALYs. Treatment with infliximab/standard care was found to be more expensive than treatment with standard care alone from the Polish National Health Fund perspective. The incremental cost-utility ratio of infliximab/standard care compared with standard care alone was estimated to be 402,420 Polish zlotys (PLN)/QALY gained (95% confidence interval [CI] 253,936-531,450 PLN/QALY gained), which is equivalent to $106,743 (U.S. dollars)/QALY gained (95% CI $67,357-140,968 [U.S. dollars]/QALY gained). Treatment with infliximab/standard care instead of standard care alone resulted in additional QALYs but also additional costs. The incremental cost per QALY gained of infliximab/standard care compared with standard care alone exceeded the willingness-to-pay threshold in Poland (equivalent to ~$33,400).

Recent advances in inflammatory bowel disease.

Recent advances in inflammatory bowel disease.

Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis. We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response. Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients. Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

Does Anti-TNF Therapy Reduce the Requirement for Surgery in Ulcerative Colitis? A Systematic Review

Infliximab has demonstrated its efficacy in moderate to severe ulcerative colitis. The Active Ulcerative Colitis Trial (ACT) -1 and 2 have demonstrated the beneficial impact of infliximab on the short-term colectomy rate. However, data evaluating this outcome beyond one year remains scarce. To provide evidence on the potential impact of infliximab on the long-term colectomy rate in patients suffering from ulcerative colitis, data was reviewed from randomized and controlled studies, referral centre studies and population-based studies, in adult and pediatric populations. In the pre-biologic era, 9-33%, 50% and 29% of adult patients with ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts, respectively. In the pediatric population, 9-61% and 8-20% underwent colectomy in referral centers and population-based cohorts, respectively. Between 10 and 36% of adult patients treated with infliximab for ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts. In the pediatric population treated with infliximab, long-term data is lacking, with colectomy rates ranging from 16 to 28%. Whether infliximab proves to be a disease modifying treatment in ulcerative colitis in the long term remains to be elucidated and will require further long-term prospective studies.

Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

Gene Expression Profiling and Response Signatures Associated With Differential Responses to Infliximab Treatment in Ulcerative Colitis

Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study. Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment (n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Expression profiling results for selected genes were confirmed using qPCR. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate T(H₁), T(H₂), and T(H₁₇) pathways. Gene expression can differentiate placebo and infliximab responders. Analysis of mRNA expression in mucosal biopsies following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.

Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab

The efficacy of infliximab for treating patients with ulcerative colitis has been established. The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo. Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy. Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Cost-utility analysis of infliximab and adalimumab for refractory ulcerative colitis

ObjectiveTo evaluate cost-utility of infliximab and adalimumab for the treatment of moderate-to-severe ulcerative colitis (UC) refractory to conventional therapies in Canada.MethodsA Markov model was constructed to evaluate incremental cost-utility ratios (ICUR) of 5 mg/kg and 10 mg/kg infliximab and adalimumab therapies compared to 'usual care' in treating a hypothetical cohort of patients (aged 40 years and weighing 80 kg) over a five-year time horizon from the perspective of a publicly-funded health care system. Clinical parameters were derived from the Active Ulcerative Colitis Trials 1 and 2. Costs were obtained through provincial drug benefit plans. ICUR was the main outcome measure and both deterministic and probabilistic sensitivity analyses were conducted.ResultsCompared to the strategy A ('usual care') in the base case analysis, the ICURs were CA$358,088/QALY for the strategy B ('5 mg/kg infliximab + adalimumab') and CA$575,540/QALY for the strategy C ('5 mg/kg and 10 mg/kg infliximab + adalimumab'). The results were sensitive to: the remission rates maintained in responders to 'usual care' and to 5 mg/kg infliximab, the rate of remission induced by adalimumab in non-responders to 5 mg/kg infliximab, early surgery rate, and utility values. When the willingness to pay (WTP) was less than CA$150,000/QALY, the probability of 'usual care' being the optimal strategy was 1.0. The probability of strategy B being optimal was 0.5 when the WTP approximated CA$400,000/QALY.ConclusionsThe ICURs of anti-TNF-α drugs were not satisfactory in treating patients with moderate-to-severe refractory UC. Future research could be aimed at the long-term clinical benefits of these drugs, especially adalimumab for patients intolerant or unresponsive to infliximab treatment.

Experience of maintenance infliximab therapy for refractory ulcerative colitis from six centres in England

Infliximab is used for treatment of Crohn's disease and, following the Active Ulcerative Colitis Trials (ACT) 1 and 2, it has been used as rescue and maintenance therapy in moderate and severe ulcerative colitis (UC). To report on English experience with maintenance infliximab in terms of response and colectomy rates and side-effect profile in UC. A retrospective audit conducted by using a web-based questionnaire filled in by 12 gastroenterologists from six English centres. Of the 38 patients receiving induction with infliximab, 28 (73.6%) maintained an ongoing response (8-weekly infusions 5 mg/kg) for a mean duration of 16.8 months (range 4-59), with 21 (55.3%) being in remission. Three of 38 patients (7.9%) who also responded had a secondary loss of response after an average of 10 months (range 8-13); seven of 38 patients (18.4%) showed no response. The colectomy rate was seven of 38 (18.4%, five non-responders and two with secondary loss of response). Adverse effects occurred in five patients (13.2%). Two discontinued infliximab (alopecia, invasive breast cancer). The three less-severe adverse effects were acute and delayed-type hypersensitivity reactions and one persistent otitis media. Our experience suggests acceptable response rates, colectomy rates and side-effect profile of maintenance therapy with infliximab in moderate and severe UC.

T1142 Infliximab Treatment for Ulcerative Colitis: Clinical Response, Clinical Remission, & Mucosal Healing in Patients with Moderate or Severe Disease in the Active Ulcerative Colitis Trials (ACT1 & ACT2)

T1142 Infliximab Treatment for Ulcerative Colitis: Clinical Response, Clinical Remission, & Mucosal Healing in Patients with Moderate or Severe Disease in the Active Ulcerative Colitis Trials (ACT1 & ACT2)

Response and remission are associated with improved quality of life, employment and disability status, hours worked, and productivity of patients with ulcerative colitis

Impairment of health-related quality of life, employment, and productivity has been documented in patients with moderate to severe ulcerative colitis. Using prospectively collected data from the Active Ulcerative Colitis Trials 1 and 2, we examined the impact of clinical response or remission, as defined using the Mayo score, on health-related quality of life, employment, disability, productivity, and hours worked per week. These analyses were based on observed data and included all 728 patients, regardless of their randomized treatment group (i.e., placebo and infliximab patients were grouped for analysis). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form (SF-36) scores among nonresponders, responders, and patients in remission were compared. In addition, changes in employment, disability status, productivity, and hours worked per week of patients in clinical remission and patients not in clinical remission were compared. Ulcerative colitis patients in clinical response or remission had significantly improved IBDQ and SF-36 scores at week 30 compared with those of nonresponders (P<0.001). Among those not employed at baseline, including those receiving disability compensation, greater percentages of patients in remission at week 30 were employed (20.6%) and not receiving disability compensation (58.8%) than were those not in remission (8.3% and 20.0%, respectively; P<0.05 for both comparisons). At week 30, improvements from baseline in productivity and both actual and fully productive hours worked per week were greater for patients in remission compared with those not in remission (P<0.05 for all three comparisons). These results confirm the validity of response and remission as defined using the Mayo score.

The Effects of Infliximab Therapy on Health-Related Quality of Life in Ulcerative Colitis Patients

The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC). In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS, respectively) scores were analyzed. Baseline scores for the pooled patient population indicated substantial impairment in HRQL. Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg (40, P < 0.001) and 10-mg/kg (36, P < 0.001) groups compared with the placebo group (28). Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS (6.8 and 5.9, respectively) and MCS (5.9 and 6.4, respectively) compared with placebo (PCS = 3.7, MCS = 3.0, P < 0.01 for all comparisons). Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy (P < 0.001 for all comparisons). Improvement in total IBDQ score correlated significantly (P < 0.001) with improvement in both PCS and MCS scores, and Mayo score. Infliximab therapy substantially improved HRQL in patients with UC. This benefit was sustained through 1 yr with maintenance infliximab therapy.

Safety of biologics in inflammatory bowel disease

Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn's disease ) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-alpha antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.

Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor α, is an established treatment for Crohn‘s disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies -the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) -evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P 0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P 0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P ≤0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of inflix imab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P0.001 for both comparisons) . CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo.

Review article: infliximab therapy for inflammatory bowel disease – seven years on

Infliximab, the chimeric monoclonal IgG1 antibody to tumour necrosis factor, is indicated for refractory luminal and fistulizing Crohn's disease and extra-intestinal manifestations of inflammatory bowel disease. Recently, the active ulcerative colitis trials (ACT) studies have shown that infliximab is also efficacious to treat ulcerative colitis resistant to standard therapy. Induction with 5 mg/kg infliximab at weeks 0, 2 and 6 is advocated. The response to infliximab is improved when concomitant immunosuppressive therapy is given. As the majority of patients will relapse if not retreated, a long-term strategy is necessary. Although episodic therapy can be used, the optimal strategy is systematic maintenance treatment with 5 mg/kg intravenous (i.v.) every 8 weeks. Long-term maintenance therapy with infliximab results in a reduction of the rate of complications, hospitalizations and surgeries associated with Crohn's disease. Safety problems with the monoclonal antibody infliximab treatment mainly concern the formation of antibodies to infliximab, which may lead to infusion reactions, loss of response and serum sickness-like delayed infusion reactions. Latent tuberculosis needs to be screened for. The rate of other opportunistic infections is slightly increased mainly in patients treated concomitantly with immunosuppression. There is no evidence that malignancy rates in patients treated with antitumour necrosis factor strategies are increased.

Infliximab for Moderate-to-Severe Ulcerative Colitis

In two multisite, randomized, double-blind, placebo-controlled, manufacturer-supported trials (Active Ulcerative Colitis Trials [ACT] 1 and 2),