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BACKGROUND Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohn's disease. METHODS PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP-ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP-ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. RESULTS Of the CZP-ADAb-positive patients, 40 (22.6%) had transient CZP-ADAbs and 94 (77.4%) had persistent CZP-ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP-ADAb-positive group relative to the CZP-ADAb-negative group. Transient CZP-ADAb-positive and CZP-ADAb-negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. CONCLUSIONS This analysis demonstrates that persistent CZP-ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

BACKGROUND & AIMS Treatments for Crohn's disease (CD) have been linked to serious infections, malignancies, and dermatologic complications. We pooled and analyzed clinical trials of certolizumab pegol, a pegylated humanized Fab' fragment against tumor necrosis factor, to quantify safety events in patients with CD. METHODS We collected data from 5 placebo-controlled trials, 9 open-label studies, and 1 dose-regimen study, conducted globally through April 2014. A total of 2570 patients with moderate to severe CD were treated with certolizumab pegol, with 4378.1 patient-years of exposure. Data were analyzed in 2 groups: patients from placebo-controlled (PC) trials treated with placebo (n = 875) or certolizumab pegol (n = 919) for 6 to 38 weeks (the PC group) or all patients exposed to certolizumab pegol (n = 2570), for durations of 6 to 362 weeks (the all-studies group). Incidence rates (IRs; incidence/100 patient-years) of adverse events (AEs) were calculated from first dose through 70 days (approximately 5 half-lives) after the last dose. RESULTS In the PC group, IRs for serious AEs were similar among patients given certolizumab pegol (31.35/100 patient-years) vs placebo (24.33/100 patient-years). IRs of serious infections or malignancies were low among patients receiving short-term treatment with certolizumab pegol (8.49/100 patient-years and 1.01/100 patient-years, respectively, in the PC group) and did not increase with long-term treatment (6.47/100 patient-years and 0.80/100 patient-years, respectively, in the all-studies group). IRs of psoriasis or psoriasiform dermatitis were low in the PC group (1.01/100 patient-years and 0/100 patient-years, respectively); in the placebo group, these IRs were 0.38 per 100 patient-years and 0 per 100 patient-years, respectively. IRs of psoriasis or psoriasiform dermatitis did not increase with long-term treatment (0.93/100 patient-years and 0.09/100 patient-years, respectively, in the all-studies group). CONCLUSIONS Based on an analysis of data pooled from 15 trials of patients with CD, the safety profile for long-term therapy with certolizumab pegol therapy is similar to that reported from short-term studies. Overall rates of AEs, serious infections, malignancies, and psoriasis did not increase with long-term treatment, suggesting a favorable risk-benefit ratio with long-term certolizumab pegol therapy in CD. Clinicaltrials.gov identifiers: NCT00291668, NCT00152490, NCT00152425, NCT00308581, NCT00349752, NCT00552058, NCT00329550, NCT00329420, NCT00160524, NCT00160706, NCT00297648, NCT00333788, NCT00307931, NCT00356408, and NCT00552344 (https://www.clinicaltrials.gov/ct2/search).

Crohn's disease is a lifelong, incurable inflammatory disease of the gastrointestinal tract that often arises in the earlier decades of life and is characterized by periods of exacerbation and remission. Tumor necrosis factor (TNF) α has a central role in the pathogenesis of inflammatory bowel diseases, and specific inhibition of this pleotropic cytokine with biological anti-TNF agents has been a major advancement in the treatment of these diseases including Crohn's disease.1,2 Anti-TNF therapy is generally well tolerated.3–5 However, because these agents have immunosuppressive properties, long-term use may increase the risk of serious infections,6 and careful consideration is given to the initiation of therapy. Only 3 anti-TNF therapies, including infliximab, adalimumab, and certolizumab pegol, are currently approved for the treatment of moderate to severe Crohn's disease in the United States. In randomized controlled trials, approximately 40% to 60% of patients with Crohn's disease had an initial response to induction therapy with anti-TNF therapy during the first 2 to 6 weeks, and of those approximately 40% to 60% were in remission after 6 months of therapy.3–5,7 However, the duration of clinical response varies widely among patients. Results of PRECiSE 2, a randomized, placebo-controlled study of certolizumab pegol maintenance therapy in patients with moderate to severe Crohn's disease, showed that approximately 40% of initial responders lost response within 6 months after treatment initiation.5 In clinical practice, 30% to 40% of patients treated with adalimumab required dose escalation; however, approximately one-third of those who received increased doses failed to maintain responses longer than 6 months.8 These examples illustrate that both primary and secondary failure to anti-TNF therapy remain significant challenges in the treatment of patients with Crohn's disease. Given the need for long-term maintenance therapy and the small number of available anti-TNF therapies, identifying strategies to maximize the benefit that a patient can derive from each agent is important. Recent studies have shown that reinduction therapy with another9 or the same10 anti-TNF agent in patients with secondary treatment failure provides clinically important short-term benefits. However, the longer-term benefit of reintroducing the same therapy to patients with primary and secondary treatment failure, including patients who previously received as little as 1 dose of induction treatment, has not been explored. Certolizumab pegol is a recombinant, humanized, polyethylene glycol–conjugated antigen-binding antibody fragment (Fab') with specificity for human TNFα. Two randomized, double-blind, placebo-controlled phase 3 studies, PRECiSE 17 and PRECiSE 2,5 demonstrated that certolizumab pegol is effective in the induction and maintenance of clinical response and remission in patients with moderate to severe Crohn's disease. Unlike patients in PRECiSE 2, who were randomized to maintenance treatment with placebo or certolizumab pegol after responding to 6 weeks of induction therapy with certolizumab pegol, patients in PRECiSE 1 were randomized to consecutive induction and maintenance treatment with either placebo or certolizumab pegol at the start of the trial. Patients who completed PRECiSE 1 or PRECiSE 2 were eligible for inclusion in PRECiSE 3, an open-label, 7-year extension study.11 In contrast, PRECiSE 4 (NCT00160706) was an open-label extension study for patients who withdrew from either treatment arm of PRECiSE 1 or PRECiSE 2 owing to exacerbation of Crohn's disease and was designed to assess the safety and efficacy of chronic certolizumab pegol therapy for up to 7 years. Here, we report efficacy and safety outcomes from the PRECiSE 4 study, which included patients with no previous exposure to certolizumab pegol, as well as patients with primary or secondary certolizumab pegol treatment failure.

SUMMARYBackground Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). Aim To identify factors that influence long-term remission of CD with CZP treatment. Methods Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey–Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. Results Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P

In Crohn's disease (CD), rapid response to anti-tumor necrosis factor therapy improves short- and medium-term outcomes, but the relationship between early remission (ER) and long-term remission is unclear.This exploratory analysis of PRECiSE 3 (NCT00160524) assessed whether ER after initiation of certolizumab pegol predicted long-term remission.Patients enrolled in PRECiSE 3 had completed PRECiSE 1 or 2, two randomized placebo-controlled studies for moderate to severe CD, and received open-label certolizumab pegol 400 mg every 4 weeks for a total treatment duration of ≤7.5 years. Time to loss of remission between patients with and without ER (Harvey-Bradshaw Index ≤4 at or before Week 6 of PRECiSE 1 or 2) was compared by log-rank test of Kaplan-Meier estimates.At baseline, patients with (n = 242) and without (n = 148) ER had mean (standard deviation [SD]) durations of CD of 6.8 (6.6) and 7.4 (7.8) years, mean (SD) CD Activity Index scores of 280.3 (53.4) and 311.1 (55.5), with 45.5% and 41.9% of patients having ileocolonic CD, and median C-reactive protein concentrations of 8.0 and 5.0 mg/L, respectively. Median certolizumab pegol plasma concentrations during the first 6 weeks of therapy were similar in both groups. Mean time to loss of remission was significantly longer in patients with versus without ER (2.77 vs. 1.14 years, p 0.0001).In certolizumab pegol-treated patients with CD, ER appears to be an important predictor of long-term clinical remission. Prospective trials are needed to determine whether ER improves other long-term outcomes.

in patients who either presented with symptomatic ileocaecal or colonic stenosis, suffering of obstructive symptoms. EBD was carried out using high-pressure Through-The-Scope Balloons with a diameter of 8-20 mm and a length of 5.5 cm, depending of the size of the strictured lumen and the endoscopists' decisions. Primary success was defined as passage of the scope through the stricture after EBD. Results: The rate of primary success was 78% (111/142) after 142 times of EBD. Forty-three (78%) of 55 patients came to need of reEBD or operations because of stenosis after the previous EBD. Additionally 16 (29%) of 55 patients came to need an operation because of a stenosis. The rate of perforation was 1.4% (2/142) in 142 times of EBD. And we compared background subjects between operation group with non-operation group. The subjects were gender, age, duration, the type of colitis, the part of dilation, 5-ASA, anti-TNFα therapy, immunomodulators, the kcal/day of Elemental diet, past surgical history, the length of stenosis, the expansion diameter, ulcer complication with stenosis. In the group which shifted to an operation, there were significantly many cases complicated with an ulcer in the stenosis department (P=0.006). anti-TNFα therapy and immunomodulators did not influence for restenosis and operation including other therapy. Conclusions: Previous studies have reported that EBD is a safe and effective approach to ileocaecal and colonic stenosis of CD patients (our study v.s. previous study; 78% v.s. approximately 80%). In our study, we found that the rate of re-stenosis and perforation were 78% and 1.4 %, similar to the previous study (24-76%, 0-11%, respectively). It is said that anti-TNF-α therapy sometimes brings stenosis, but, any treatment including anti-TNF-α therapy did not influence for restenosis and operation. In our study, we have found that the length of stenosis and the expansion diameter did not influence for operation. We have suggested that stenosis complicated with ulcer was a risk factor for operation after EBD.

Back ground: The calcineurin inhibitor (CNI) tacrolimus (TAC) has been reported to be effective for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). However, CNI has nephrotoxic potential leading to acute and chronic renal damage in some cases. To date, little is known about the influence of long term administration of oral TAC on renal function in patients with UC. Aim: The aim of our study was to evaluate the incidence and the severity of renal function impairment in UC patient who received TAC treatment. Methods: In this retrospective study, the medical charts of 71 adult patients with steroid-refractory UC treated with TAC between 2012 and 2014 in a single Japanese center were analyzed. In principle, TAC was orally administrated as a 2 week-induction (target trough levels 10-15ng/ml) followed by a maintenance therapy (target trough levels 5-10ng/ml). Estimated glomerular filtration rate (eGFR) was evaluated during the treatment. Acute kidney injury (AKI) was defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of function, Loss of function and End-stage kidney disease) consensus criteria using the maximal change in serum creatinine (Scr) and eGFR during the TAC treatment compared with baseline value before treatment. Results: The mean duration of TAC administration was 210 days. At 12weeks, TAC produced a clinical response in 54 patients (76.1%) and remission was achieved in 29 of those 54 (40.8%). The AKI rate during TAC treatment was 46.5% (33 of 71 patients). RIFLE class R (Scr increase > 1.5 times or eGFR decrease > 25%) accounted for 27 patients (38.0%), and RIFLE class I (Scr increase > 2 times or eGFR decrease > 50%) for six (8.5%). The AKI rate was 76.8% (10/13) in patients who had been administrated TAC for more than 1 year and 37.5% (18/48) in patients with TAC treatment within 6 months (p=0.006). After withdrawal of TAC, renal function impairment (eGFR decrease > 25%) was still observed in 10 patients (14.1%). Conclusions: Oral TAC therapy appears to be effective for patients with refractory UC. However, renal function impairment was frequently observed during this treatment. Thus, careful monitoring of renal function must be required to avoid irreversible chronic renal damage during long-term administration of TAC.