Concurrent Immunomodulator Research Articles

Open Label Ustekinumab for the Treatment of Anti-TNFα Refractory Moderate-to-Severe Crohnʼs Disease

Purpose: Ustekinumab is a monoclonal antibody against the shared p40 subunit of interleukin-12/23 which has been demonstrated to produce clinical response in patients with moderate-to-severe Crohn's disease (CD) with induction dosing in a phase 2a study. Since its approval by the FDA in September 2009 for the treatment of psoriasis, the drug has been used off-label as a treatment for anti-TNFα refractory CD outside the context of clinical trials. This is the first series describing post-marketing use of ustekinumab in patients with moderate-to-severe CD at an academic medical center. Methods: Patients were identified who had received at least 2 doses of ustekinumab for the treatment of moderate-to-severe Crohn's disease. Patients received 45 mg or 90 mg subcutaneous doses at weeks 0 and 4 and then were dosed at intervals of 8 or 12 weeks at the physician's discretion. Baseline demographics were recorded and Harvey Bradshaw Index (HBI) was prospectively recorded on each patient. The primary endpoint was clinical response, defined by a decrease in HBI ≤ 3 at week 12. Secondary endpoints included remission (HBI ≤ 3) and ability to taper steroids at week 12. Results: A total of 13 patients met inclusion criteria and 9 patients have been on therapy ≥12 weeks. Prior infliximab failure was documented in 11/13 (84%) of patients with 5/11 (45%) having had failed 10 mg/kg dosing. None of the patients were infliximab primary non-responders. Additionally, 11/13 (84%) had failure to two or more anti-TNFα formulations. None of the patients were on concurrent immunomodulator therapy with ustekinumab. Mean duration of ustekinumab was 25.6 ± 16.6 weeks. At week 12, clinical response was found in 7/9 (77.8%) patients (p<0.05). Clinical remission was achieved in 4/9 (44.4%). Two patients were on steroids prior to initiation of ustekinumab; both were able to taper their steroids and one was able to discontinue steroids completely by week 8. No adverse drug reactions were noted. Conclusion: Ustekinumab is a promising therapy for moderate-to-severe Crohn's disease in patients who have previously failed anti-TNFα therapy. Further studies exploring optimal dosing regimens for induction and longer term studies on maintenance are needed.

Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

Background Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. Objectives The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohn's disease (CD) from 2 Phase III studies. Methods This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6–76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease] and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. Results Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; V d in the central compartment (V 1), 54.2 (1.15) mL/kg; V d in the peripheral compartment (V 2), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V 1, 52.7 (0.49) mL/kg; V 2, 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V 2 decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t 1/2 (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults. Conclusions Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator coadministration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6–76 years).

Effectiveness of temporary dose increase at recapturing response in patients on maintenance infliximab

IntroductionBiologic drugs are widely used in Crohn's disease, often with good effect. Unfortunately, even with scheduled maintenance therapy, secondary loss of response is common affecting approximately 10–15% of patients/year. There...

Long-term Durability of Infliximab Treatment in Crohn's Disease and Efficacy of Dose “Escalation” in Patients Losing Response

The efficacy of infliximab therapy in patients with Crohn's disease (CD) is unknown beyond 12 months. For patients who lose their initial response, consideration can be given to dose "escalation" to regain therapeutic benefit. Our primary goal was to evaluate the long-term durability of maintenance infliximab treatment. The secondary goals were to identify potential predictors of loss of infliximab efficacy, to evaluate the response to infliximab escalation, and the safety of the treatment with infliximab with and without escalation of dose. CD patients treated with infliximab with response to an induction regimen were evaluated. Maintenance of long-term response was estimated using Kaplan-Meier analysis. The effect of specific variables was calculated using logistic regression analysis. Efficacy of dose escalation in patients who lose response to infliximab was analyzed. Three hundred and nine CD patients were included. The mean follow-up time with infliximab treatment was 41 months, and the majority (95%) were on concomitant immunosuppressive therapy. The annual risk of loss of response to infliximab was 12% per patient-year of treatment. After loss of response, 41% of patients were managed with infliximab therapy escalation. After the first intensified dose, 56% of patients achieved remission and 40% partial response. Concurrent immunomodulators enhanced and smoking decreased the proportion of patients who maintained response (P<0.05). A relevant proportion of CD patients on long-term infliximab treatment loss response. After loss of response, a high proportion of these patients initially respond to infliximab dose escalation. Concurrent immunomodulators may increase and smoking may decrease maintenance of response.

Systematic review: does concurrent therapy with 5‐ASA and immunomodulators in inflammatory bowel disease improve outcomes?

With greater use of immunomodulators in inflammatory bowel disease (IBD), it is uncertain whether concurrent therapy with both 5-aminosalicylic acid [5-ASA, mesalazine (mesalamine)] and an immunomodulator is necessary. To determine whether concurrent therapy with both 5-ASA and immunomodulator(s) improves outcomes in IBD. Systematic review with search terms 'azathioprine, 6-mercaptopurine, thiopurine(s), 5 aminosalicylic acid, mesalazine, inflammatory bowel disease, ulcerative colitis, Crohn's disease, immunosuppressant(s), immunomodulator and methotrexate' in November 2007 to identify clinical trials on concurrent 5-ASA and immunomodulator therapy. Two small controlled studies were found. Neither showed a benefit on disease control beyond immunomodulator monotherapy. Potential pharmacological interactions exist between 5-ASA and thiopurines. Whilst circumstantial, epidemiological and laboratory evidence suggests that 5-ASA may assist colorectal cancer (CRC) chemoprevention, it may simply be via anti-inflammatory effects. With changes in practice, ethical issues and the long lead-time needed to demonstrate or disprove an effect, no clinical studies can/will directly answer this. The costs of avoiding one CRC in IBD may be as low as 153 times the annual cost of 5-ASA therapy. It is unclear whether concurrent 5-ASA and immunomodulator therapy improves outcomes of disease control, drug toxicity or compliance. Concurrent therapy of 5-ASA and immunomodulators may decrease CRC risk at 'acceptable' cost.

Natalizumab: benefit outweighs risk in selected patients with multiple sclerosis

Natalizumab: benefit outweighs risk in selected patients with multiple sclerosis

Long-Term Durability of Crohn’s Disease Treatment with Infliximab

There is a paucity of data providing insight into the durability of Crohn's disease treatment with infliximab for periods longer than 12 months. Our aim was to assess the long-term durability of infliximab therapy. A total of 198 Crohn's patients under a maintenance regimen with infliximab, with at least a 30-month follow-up, were evaluated retrospectively. Long-term response maintenance was estimated using Kaplan-Meier analysis. The effect of specific variables was calculated using logistic regression and proportional hazard regression analyses. Maintenance of response rates at 72 months was estimated to be 66.4% for initial responders and 58.2% for all patients treated. Concurrent immunomodulators enhanced response maintenance in all patients treated, particularly if started >3 months before the initiation of infliximab therapy. Smoking significantly decreased the maintenance of response in initial responders. Infliximab treatment of Crohn's disease is reasonably durable beyond 12 months. Concurrent immunosuppressive therapy may increase - and smoking may decrease - long-term response maintenance.

This Month in Gastroenterology

This Month in Gastroenterology

Induction and Maintenance Infliximab Therapy for the Treatment of Moderate-to-Severe Crohn’s Disease in Children

The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease. Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54. At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.

Efficacy of Infliximab in Ulcerative Colitis in a Clinical Practice Setting

Purpose: Infliximab has recently been approved for use in moderate and severely active ulcerative colitis(UC) on the basis of two randomized controlled trials. We aim to evaluate the drug in routine practice to ascertain if outcomes are similar in everyday clinical use. Methods: We reviewed the charts of patients treated with infliximab for UC at one center over 3 years. Results: We identified 42 patients (20 male, 22 female), with an average age of 36.9 years, who received 146 infusions. The average duration of disease prior to first infusion was 7.5 years (3 months-27 years). The leading indications for infliximab use were steroid refractory or steroid dependent disease. 67% of patients were being treated with concurrent immunomodulators at baseline. 32 patients had sufficient data for follow-up of symptoms after infusion of infliximab and a modified Mayo score measuring stool frequency and rectal bleeding (range 0–6, with 6 being most severe) was calculated from data collected at baseline and follow-up visits. The mean time to follow-up after 1st infusion was 11 weeks. Sigmoidoscopy or colonoscopy was documented in 14 patients within 3 months prior to therapy; 6 had pancolitis, 6 – left sided colitis, 1 – proctitis and 1 – pouchitis. 23 patients were on steroids at time of 1st infusion at a mean dose of 24.7 mg of prednisone. At follow-up, the mean dose of steroids had decreased to 19.9mg of prednisone. 17% of patients were able to discontinue steroids. 71% of patients had a clinical response as measured by decrease in stool frequency and/or bleeding. 22% of patients were in remission as defined by normal stool frequency, absence of rectal bleeding and no use of steroids. The mean modified Mayo score decreased from 3.9 at baseline to 1.4 at follow-up. However, 22% of patients required colectomy at a mean of 43 days after 1st infusion. 12% of patients required dose escalation to maintain response. Conclusions: Our data show that the majority of patients have some improvement after infliximab. However, the important clinical endpoints of remission or steroid withdrawal occur in less than a quarter of patients. In this short term study 22% of patients required a colectomy. These findings are consistent with data obtained in larger randomized controlled studies and suggests those results can be applied to patients encountered in clinical practice.

Association of Trough Serum Infliximab to Clinical Outcome After Scheduled Maintenance Treatment for Crohn’s Disease

The effect of infliximab infused at scheduled intervals on antibody formation, preinfusion trough serum concentrations of infliximab, and their clinical significance was evaluated in patients with Crohn's disease. Antibodies to infliximab and trough serum infliximab were measured in 105 patients with Crohn's disease treated with 5 mg/kg infliximab for induction followed by maintenance episodic re-treatment (n = 23) or scheduled therapy at 6- to 8-week intervals (n = 82). After a median of 14 infusions (range, 2-45), 21% of patients had detectable antibodies, 25% were antibody negative, and 54% were antibody inconclusive. Antibody formation was higher after episodic compared with scheduled treatment (39% vs 16%; P = .036) and was associated with a higher rate of infusion reactions (50% vs 21%; P = .018). Ninety patients continued maintenance scheduled therapy beyond 12 months including 12 converted episodic patients, with a median follow-up of 23 months (range, 16-68 months). The rate of clinical remission was higher for patients with a detectable trough serum infliximab compared with patients in whom serum infliximab was undetectable, including those without antibodies (82% vs 6%; P < .001). A detectable trough serum infliximab was also associated with a lower C-reactive protein (2.0 vs 11.8 mug/L; P < .001) and a higher rate of endoscopic improvement (88% vs 33%; P < .001). Concurrent immunomodulators did not alter outcomes. For Crohn's disease patients treated with scheduled maintenance infusions of infliximab, the trough serum concentration of infliximab predicts clinical outcome. Factors in addition to antibody formation, likely pharmacokinetic, modulate serum infliximab and thus the response to infliximab therapy.

Comparison of Safety and Mortality of Infliximab Therapy to Immunomodulator Therapy in Crohnʼs Disease

Purpose: While infliximab is indicated for the treatment of Crohn's disease, blockade of TNF may result in severe immune suppression. Several case series suggested an increase in severe infections, malignancy, and possibly mortality in patients receiving infliximab. Our aim was to assess serious complications in Crohn's disease patients receiving infliximab compared to Crohn's disease patients receiving immunomodulator therapy. Methods: We searched all the patients seen at the Cleveland Clinic between 1999 and 2003 with a diagnosis of Crohn's disease. We included all 322 eligible patients who received at least one dose of infliximab with or without concurrent immunomodulators (the infliximab group) and compared with 217 patients who received 6-mercaptopurine (6MP), azathioprine (AZA), methotrexate (MTX) or corticosteroids for at least 3 consecutive months (the immunomodulator group). We compared the frequency of severe infection, neoplasm, and mortality between the 2 groups. The exclusion criteria were 1) age < 20 at the time of entry; 2) enrollment in the ACCENT trials; and 3) infliximab infusion for diseases other than Crohn's disease. Severe infection was defined as an infection which occurred within 2 months of the last infliximab infusion requiring hospitalization and IV antibiotics, infection by opportunistic organisms or causing a near death experience. All neoplasms were included except basal cell carcinoma. Results: The 2 groups were comparable in age, gender, disease location, and mean number of IBD- related surgeries (2.1 ± 3.2 vs 1.7 ± 1.9). In the infliximab group, 322 patients received a total of 2168 infusions with a mean follow-up of 2 years after the start of infliximab therapy and a mean of 13.7 years since diagnosis. 26.7% of patients received infliximab prior to any other immunomodulators and 11.8% of patients received no concurrent immunomodulators. Of 217 patients in the immunomodulator group with a mean follow-up of 15.6 yrs since diangosis, 48.4% had 6MP/AZA, 5% had steroids, 4.1% had MTX, 42.5% received more than one immunomodulators. Conclusions: There were no statistical differences in the frequency of severe infection, neoplasm, and mortality in Crohn's disease patients between the infliximab and immunomodulator groups. Mortality of the 2 groups was 2.5% and 1.8% respectively.Table: No Caption available.

ABNORMALITIES OF THE UTERINE CERVIX IN WOMEN WITH IBD

Purpose: To evaluate prevalence of abnormalities of the uterine cervix in women with inflammatory bowel disease (IBD) when compared to healthy controls. Methods: 93 patients with IBD [46 Crohn's disease (CD), 45 Ulcerative colitis (UC), 2 indeterminate colitis] were age matched (± two years) to 93 healthy controls. Cases and controls were of middle to high socio-economic status. Data was collected forage, race, marital status, diagnosis of IBD with duration, severity, and use of immunomodulators. Pap smear results for five years prior to enrollment were obtained and results were categorized as normal, “of unknown significance,” and abnormal (dysplasia or carcinoma). For data analysis purposes, “abnormal” and “of unknown significance” results were grouped into one category. Results: Mean age at the time of pap was 44 years (SD ± 13) and median duration of IBD was 15 years (0–55). Majority of the patients were Caucasian (90% cases vs. 82%) and married (73% vs. 63%). 58% of IBD patients had received past or concurrent immunomodulators (6-mercaptopurine, imuran, or infliximab). Univariate analysis showed a trend toward a higher occurrence of abnormal pap (9% vs. 3%) and pap “of unknown significance” (6% vs. 2%) in the IBD group as compared to the controls (p = 0.06). Severity of IBD correlated positively with abnormal pap smear (r = 0.17, p = 0.02). No significant correlation was observed between exposure to immunomodulators and age with abnormal pap results (p >0.20). Subgroup analysis for CD and UC revealed an equal distribution of abnormal pap results in the two groups (p >0.80). Multivariate analysis predicting abnormal pap results was performed using the following variables: diagnosis of IBD (present or absent), age at the time of pap test and previous or concurrent exposure to immunomodulators. The overall model tended towards significance (p = .06) although the diagnosis of IBD appeared to be the only meaningful predictor of outcome (OR = 4, 95% CI 1.23 – 14.5; p = 0.02). Conclusions: Diagnosis of IBD bears a relationship with abnormal pap smear results while age and exposure to immunomodulators do not. Women with IBD should be screened regularly with pap smears because of the possible increased prevalence of abnormal finding.

CONCURRENT IMMUNOMODULATOR THERAPY IN CROHNʼS DISEASE; DOES IT IMPROVE INITIAL RESPONSE TO INFLIXIMAB?

Purpose: It has been proposed that concurrent immunomodulator (IM-MUNO) rx may improve long term response to rx with infliximab (INFLIX) by reducing antibody formation against INFLIX. What impact IMMUNO rx has on the initial response to INFLIX rx is less clear. Aim: To determine if concurrent IMMUNO rx improves the initial complete response to INFLIX in Crohn's disease (CD). Methods: A retrospective cohort analysis of 137 pts who received INFLIX for rx of their active CD (1/'99 - 1/'02). Clinical outcome definitions: complete response (achieved previous baseline), partial response (> 50% improvement), and no response (no/minimal change in symptoms) as assessed by patients and physicians. Concurrent IMMUNO therapy was defined as being treated with IMMUNO rx at the 1st infusion of INFLIX. Smoking definition: >7 cigarettes per wk within 6 mos of INFLIX treatment. Logistic regression was used to adjust for potential confounders including sex, age, duration of disease, smoking, presence of stricture, prior bowel resection, and disease location. Results: 6MP/AZA was used at the time of infusion in 66 (48%) pts. Of these 66 pts, 32(48%)had a complete response and 23 (35%) had apartial response. The duration of response to INFLIX did not statistically differ amongst pts who had used 6MP/AZA previously or who were naive to 6MP/AZA. Among the 71 pts not currently on 6MP/AZA, 41 (58%) had a complete response and 21 (30%) had a partial response. The relative risk of having a complete response given concurrent 6MP/AZA use was 0.84 (95% CI 0.61-1.15). After adjusting for potential confounders, use of 6MP at the time of the initial INFLIX infusion was not associated with complete response (OR = 0.72, 95% CI 0.34-1.54). The mean duration of complete response was similar in those not receiving 6MP/AZA at the time of initial infusion (2.3 mos vs 2.6 mos, p = 0.38 by t-test). Conclusions: IMMUNO rx concurrent with INFLIX treatment was no more effective than INFLIX therapy alone for obtaining a complete response during the initial 12 wks of therapy. In addition, the duration of response to INFLIX did not differ amongst pts using 6MP who had prior 6MP use or who were naive to 6MP. This data suggests that concurrent IMMUNO rx with INFLIX did not add benefit to pts initial response to INFLIX rx. Future prospective trials should test this further.

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?