Anti-tumour Necrosis Factor Alpha Agents Research Articles

Long-term safety of brazikumab in the open-label period of a randomized phase 2a study of patients with Crohn’s disease

BackgroundShort-term efficacy and safety of brazikumab (MEDI2070), a human monoclonal antibody and anti-p19 subunit inhibitor of interleukin-23, was demonstrated in a phase 2a trial in patients with moderate-to-severe active Crohn’s disease (CD). We report brazikumab long-term safety and tolerability from the open-label period of this phase 2a study.MethodsPatients who completed the 12-week, double-blind induction period were eligible for inclusion in an open-label period where all patients received subcutaneous brazikumab (210 mg) every 4 weeks for 100 weeks. Patients had moderate-to-severe active CD and had failed or were intolerant to ≥ 1 anti-tumour necrosis factor alpha (TNFα) agent. Safety assessments included treatment-emergent adverse events (TEAEs); further assessments were pharmacokinetics and immunogenicity.ResultsOf the 104 patients who entered the open-label period, 57 (54.8%) continued to the end of the open-label period and 47 (45.2%) discontinued brazikumab. The most common reasons for discontinuation were lack of response (14.4%), patient decision (12.5%), and TEAEs (11.5%). In total, 44 (84.6%) in the group switching from placebo to brazikumab (placebo/brazikumab) and 43 (82.7%) in the group continuing brazikumab (brazikumab/brazikumab) experienced 1 or more TEAEs. Most TEAEs were mild-to-moderate in severity. Common TEAEs included nasopharyngitis and headache. Numbers of treatment-emergent serious adverse events (TESAEs) were similar between groups. Infections occurred in 40.4% of patients in the placebo/brazikumab group and 50% in the brazikumab/brazikumab group. There were 5 TESAEs of infection, none of which were opportunistic. No major adverse cardiac events, malignancies, or deaths were reported.ConclusionsBrazikumab was well tolerated with an acceptable safety profile over a 100-week period in patients with moderate-to-severe active CD who failed or were intolerant to 1 or more anti-TNFα agents.Trial registrationNCT01714726; registered October 26, 2012.

Ustekinumab Versus Anti-tumour Necrosis Factor Alpha Agents as Second-Line Biologics in Crohn's Disease

BackgroundThere are little data on positioning biologics in Crohn's disease (CD).AimsWe aimed to assess the comparative effectiveness and safety of ustekinumab vs tumour necrosis factor-alpha (anti-TNF) agents after first-line treatment with anti-TNF in CD.MethodsWe used Swedish nationwide registers to identify patients with CD, exposed to anti-TNF who initiated second-line biologic treatment with ustekinumab or second-line anti-TNF therapy. Nearest neighbour 1:1 propensity score matching (PSM) was used to balance the groups. The primary outcome was 3-year drug survival used as a proxy for effectiveness. Secondary outcomes included drug survival without hospital admission, CD-related surgery, antibiotics, hospitalization due to infection and exposure to corticosteroids.ResultsSome 312 patients remained after PSM. Drug survival at 3 years was 35% (95% CI 26–44%) in ustekinumab compared to 36% (95% CI 28–44%) in anti-TNF-treated patients (p = 0.72). No statistically significant differences were observed between the groups in 3-year survival without hospital admission (72% vs 70%, p = 0.99), surgery (87% vs 92%, p = 0.17), hospital admission due to infection (92% vs 92%, p = 0.31) or prescription of antibiotics (49% vs 50%, p = 0.56). The proportion of patients continuing second-line biologic therapy did not differ by reason for ending first-line anti-TNF (lack of response vs intolerance) or by type of first-line anti-TNF (adalimumab vs infliximab).ConclusionBased on data from Swedish routine care, no clinically relevant differences in effectiveness or safety of second-line ustekinumab vs anti-TNF treatment were observed in patients with CD with prior exposure to anti-TNF.

P147 Trends in choice of first line biologic therapy for patients with Inflammatory Bowel Disease. An observational cohort study

Abstract Background Biologic therapies have revolutionised the management of Inflammatory Bowel Disease (IBD) with increasing utilisation over the last decade. The anti-Tumour Necrosis Factor-alpha (anti-TNF) agents (Infliximab (IFX) and Adalimumab (ADA)) as well as newer agents (Ustekinumab (UST) and Vedolizumab (VED)) all have well demonstrated safety and efficacy profiles in the management of IBD. The choice of an optimal first line biologic remains unclear due to lack of comparative randomised trials and real-world studies; however, certain patient and disease characteristics may influence this choice. The aims of this study were to explore temporal trends in choice of 1st-line biologic therapy and factors that influence this choice. Methods A retrospective observational cohort study of all patients with IBD that commenced induction and completed at least one maintenance dose of a biologic therapy between 1st January 2015 and 31st December 2021. Relevant patient and disease-specific factors were collected, including patient comorbidities (ischaemic heart disease, malignancy and opportunistic infections) at time of diagnosis, for each eligible patient. Factors affecting choice of biologic therapy were compared using ANOVA and c2 test. Results 280 patients were included, with 50.7% being male and median age of IBD diagnosis of 29 years. There was a progressive increase in biologic use over time, with 15 patients commencing1st biologic therapy in 2015, rising to 58 patients in 2021. UST has overtaken IFX and ADA as first line choice for Crohn’s disease (CD) since its introduction in 2018 (Figure 1). IFX has remained preferred first line therapy for ulcerative colitis (UC) over VED and ADA, with stable trend in choice over time. Factors with significant differences in choice of first line biologic therapy included age (UST for older age of commencement), IBD subtype (higher proportion of patients commencing ADA had CD, whereas higher proportion of patients commencing VED had UC), disease location (VED was preferred for colonic over ileal CD), and malignancy (UST was preferred) (Table 1). Conclusion - There has been a steady rise in the number of patients commencing biologic therapies, with an average increase of 24% per year from 2015 to 2021. - Ustekinumab has replaced anti-TNF therapy as the preferred first line biologic for Crohn’s disease; a trend likely secondary to the comparatively favourable safety profile of ustekinumab. Ustekinumab was preferred in older patients and those with history of malignancy. - Infliximab remains the preferred first line therapy for ulcerative colitis with stable trends in choice. - The presence of perianal disease was not a significant factor affecting choice.

The inexorable increase of biologic exposure in paediatric inflammatory bowel disease: a Scottish, population-based, longitudinal study.

The use of biologics in paediatric-onset inflammatory bowel disease (PIBD) is rapidly changing. To identify the incidence and prevalence of biologic use within Scottish PIBD services, and to describe patient demographics and outcomes for those patients who required escalation of therapy beyond anti-tumour necrosis factor alpha (anti-TNFα) agents METHODS: We captured a nationwide cohort of prospectively identified patients less than 18 years of age with PIBD (A1 phenotype; diagnosed <17 years of age) within paediatric services over a 4.5-year period (1 January 2015-30 June 2019). All patients who received infliximab, adalimumab, vedolizumab or ustekinumab during the study period and/or received their first dose of these biologics were audited retrospectively. Scotland-wide PIBD-prevalence cases increased from 554 to 644 over the study period. A total of 495 incident new-start biological therapies were commenced on 403 PIBD patients: 295 infliximab (60%), 161 adalimumab (32%), 24 vedolizumab (5%) and 15 ustekunumab (3%). The proportion of new-start biologics changed with infliximab initiation rates decreasing (87%-54%) while adalimumab (13%-31%), vedolizumab (0%-9%) and ustekinumab (0%-6%) all increased. The incidence rate (first dose of new biologic not including biosimilar switch) increased from 6.9% to 8.1% over the study period and point prevalence rates (any biologic use) increased from 20.2% to 43.5% - an average annual percentage increase of 20%. Biosimilar penetration of new-start anti-TNFα agents increased from 3% to 91%. Demographics and outcomes of those patients receiving vedolizumab and ustekinumab were similar. Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing, inexorably increasing PIBD biologics landscape.

DOP70 Anti-TNF withdrawal according to a risk-stratified protocol does not reduce the risk of relapse in patients with Inflammatory Bowel Disease in endoscopic remission: A prospective study

Abstract Background Discontinuation of anti-tumour necrosis factor alpha agents (anti-TNF) in patients with inflammatory bowel disease (IBD) in remission may reduce side effects and costs, but this has to be weighed against the risk of relapse. We developed a risk-stratified protocol for anti-TNF withdrawal, and aimed to assess the risk of relapse after risk-stratified anti-TNF withdrawal. Methods This was a single arm prospective observational cohort study. Patients were recruited between September 2018–2020 in 13 hospitals in the Netherlands. Inclusion criteria were a diagnosis of IBD, age &amp;gt;18 years, elective anti-TNF withdrawal in a patient with quiescent disease (according to the treating physician), no current or planned use of vedolizumab, ustekinumab or tofacitinib, no hospitalization, and no active or planned pregnancy. According to the protocol, patients were recommended to withdraw anti-TNF only when in endoscopic remission either without high-risk criteria (age at diagnosis &amp;lt;18 years, and for Crohn’s disease [CD]: smoking, stricturing/penetrating disease behaviour, small bowel resection &amp;gt;50cm), or when trough levels were undetectable. We constructed Kaplan-Meier curves with log-rank test to compare the risk of relapse in patients who discontinued anti-TNF in accordance with, versus against, the protocol. Cox regression analysis was performed to identify predictors of relapse. Results We enrolled 115 patients (CD: n=61, 53%), with a median follow-up time of 1.9 (IQR 1.8 – 2.1) years. Baseline endoscopic remission was confirmed in 103 (89.6%) patients, and 35 (30.4%) patients continued an immunomodulator. During follow-up, 57 (49.6%) patients relapsed (Figure 1). The relapse rate was similar in patients in endoscopic remission who withdrew anti-TNF in according with, versus against, the protocol (50.7% versus 44.4%, p=0.65), and in patients with versus without an immunomodulator (hazard rate [HR] 0.89, 95%CI 0.50 – 1.59), but was lower in patients with subtherapeutic anti-TNF trough levels (adjusted HR: 0.55, 95%CI: 0.31 – 0.99), and in patients with UC/IBD-unclassified (IBDU) who were treated with mesalamine maintenance therapy (HR: 0.35, 95%CI 0.13 – 0.94). Anti-TNF was reintroduced in 41 (71.9%) patients, with remission rates of 64.5% and 81.8% at 3 and 12 months, respectively. In 6 (15.0%) patients anti-TNF therapy was discontinued again due to primary non-response or loss of response. Conclusion The risk of relapse after anti-TNF withdrawal remains high in a strictly selected group of patients with uncomplicated IBD in endoscopic remission. Therapeutic drug monitoring prior to anti-TNF withdrawal, and mesalamine therapy for patients with UC or IBDU, may reduce the risk of relapse.

P320 6-Thioguanine nucleotide levels are associated with trough levels of infliximab and adalimumab in Inflammatory Bowel Disease patients on combination therapy: A retrospective multicentre study

Abstract Background Thiopurine co-therapy with anti-tumour necrosis factor alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in patients with Inflammatory Bowel Disease (IBD). However, the, 6-thioguanine nucleotide (6-TGN) threshold level required to confer this benefit remains unclear. We aimed to evaluate the relationship between serum, 6-TGN levels and trough levels of infliximab (IFX) and adalimumab (ADA) in IBD patients on combination therapy. Methods We performed a retrospective multicentre study of IBD patients receiving combination anti-TNFα and thiopurine maintenance therapy, for at least, 3 months duration with stable doses for at least, 2 months. All, 6-TGN levels measured within, 3 months prior to or on the same date as IFX or ADA trough levels, between January, 2015 and August, 2021, were included. Undetectable 6-TGN levels (&amp;lt;5pmol/8x108 RBC) were excluded. Patient demographics, disease characteristics, treatment details, biochemical results, and endoscopy results were collected. Primary outcomes were IFX and ADA levels. Secondary outcomes were antibodies to IFX (ATI) or ADA (ATA). Spearman’s rho was used to correlate, 6-TGN and anti-TNFα levels. The Mann-Whitney U test was used to compare anti-TNFα levels between, 6-TGN quartiles, and, 6-TGN levels between patients with and without detectable ATI. Results 483 paired, 6-TGN and anti-TNFα levels (426 IFX, 57 ADA) from, 266 patients (217 IFX, 49 ADA) were included. The median, 6-TGN level was, 240pmol/8x108 RBC, median IFX level was, 6.55mcg/ml and median ADA level was, 7.60mcg/ml. There were significant positive correlations between, 6-TGN and IFX levels (rho, 0.147, p=0.003), and, 6-TGN and ADA levels (rho, 0.266, p=0.047). Figure, 1 shows median IFX levels stratified by, 6-TGN quartiles (Q1:, 0–156, Q2:, 157–237, Q3:, 238–331 and Q4: &amp;gt;331pmol/8x108 RBC). There was a significant difference in IFX levels between Q2 and Q3 (p=0.017), but not between Q1 and Q2 (p=0.232), or Q3 and Q4 (p=0.544). Figure, 2 shows median ADA levels stratified by, 6-TGN quartiles (Q1:, 0–183, Q2:, 184–252, Q3:, 253–352, Q4: &amp;gt;352pmol/8x108 RBC). ADA levels did not differ significantly between, 6-TGN quartiles., 6 patients had detectable ATI. Of these, 5 patients had, 6-TGN levels in Q1 and, 1 patient had a, 6-TGN level in Q2. Patients with ATI had significantly lower, 6-TGN levels compared to those without ATI (median, 6-TGN, 147 vs, 239.5pmol/8x108 RBC, p=0.017). No patients had detectable ATA. Conclusion 6-TGN levels are associated with IFX and ADA trough levels. Target, 6-TGN levels in the lower end of the therapeutic range may be adequate to maintain anti-TNFα levels and prevent anti-drug antibodies in combination therapy.

The Impact of Anti-tumour Necrosis Factor Alpha Agents on the Risk of Colorectal Cancer.

The Impact of Anti-tumour Necrosis Factor Alpha Agents on the Risk of Colorectal Cancer.

P540 Real-world evidence on treatment switching in patients with moderate-to-severe ulcerative colitis: a systematic review of literature

Abstract Background Current approved therapies for the treatment of moderate-to-severe ulcerative colitis (UC) have well-established efficacy; however, some patients may fail to respond or may lose their response over time, resulting in dose escalation or treatment switching. The objective of this systematic literature review was to summarize the real-world evidence on treatment switching in UC and the associated clinical, safety and economic outcomes. Methods A literature search of Embase and MEDLINE (from database inception to August 2020) and conference proceedings (2017 to 2020) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The population of interest included adult patients (≥18 years) with UC who experienced treatment switching on anti-tumour necrosis factor alpha agents (anti- TNFα) - (adalimumab [ADA], infliximab [IFX], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOFA), and ustekinumab (USTE). Outcomes of interest included all available clinical, safety and economic outcomes. Results Of a total 1593 studies screened, 29 met the eligibility criteria. Of these, 22 (76%) reported switching rates of 4–63% (sample size: 4-1274). A total of 7 studies reported outcomes in populations comprised entirely of switched patients (sample size: 5–76). Figure 1 includes the directed connectivity graph showing the number of studies reporting different switches. IFX to ADA was the most frequently reported switch (n=11 studies;35%). Figure 2 and Table 1 include the number of studies and proportion of patients reporting outcomes following a treatment switch, respectively. Heterogeneity was observed in patient populations, follow-up, and definitions of response/remission. In the short term (4–12 weeks), remission rates of 10–38% have been reported that increased to 49–100% in the long-term (24–57 weeks). In contrast, the clinical response rates decreased over time (30–58% over 4–12 weeks versus 15–56% over 24–57 weeks). Colectomy and corticosteroid-free remission were reported in 0–35% and 18–79% of patients, respectively. Rate of adverse events varied from 13–38%, with a switch to IFX from other anti-TNFs associated with the highest rate. One study reported higher mean quarterly total healthcare costs in patients who switched within anti-TNFs (IFX&amp;gt;ADA, ADA&amp;gt;IFX) compared to those who did not ($15,004 vs $9632). Conclusion Treatment switching in the management of moderate-to-severe UC is common in routine clinical practice and is associated with suboptimal outcomes and potentially increased costs. There remains a need for additional treatment options that provide long-term durable disease control.

Long-term outcomes of acute severe ulcerative colitis in the rescue therapy era: A multicentre cohort study.

BackgroundThe long‐term course of ulcerative colitis after a severe attack is poorly understood. Second‐line rescue therapy with cyclosporine or infliximab is effective for reducing short‐term colectomy but the impact in the long‐term is controversial.ObjectiveThe purpose of this study was to evaluate the long‐term course of acute severe ulcerative colitis patients who avoid early colectomy either because of response to steroids or rescue therapy.MethodsThis was a multicentre retrospective cohort study of adult patients with acute severe ulcerative colitis admitted to Italian inflammatory bowel disease referral centres from 2005 to 2017. All patients received intravenous steroids, and those who did not respond received either rescue therapy or colectomy. For patients who avoided early colectomy (within 3 months from the index attack), we recorded the date of colectomy, last follow‐up visit or death. The primary end‐point was long‐term colectomy rate in patients avoiding early colectomy.ResultsFrom the included 372 patients with acute severe ulcerative colitis, 337 (90.6%) avoided early colectomy. From those, 60.5% were responsive to steroids and 39.5% to the rescue therapy. Median follow‐up was 44 months (interquartile range, 21–85). Colectomy‐free survival probability was 93.5%, 81.5% and 79.4% at 1, 3 and 5 years, respectively. Colectomy risk was higher among rescue therapy users than in steroid‐responders (log‐rank test, p = 0.02). At multivariate analysis response to steroids was independently associated with a lower risk of long‐term colectomy (adjusted odds ratio = 0.5; 95% confidence interval, 0.2–0.8), while previous exposure to antitumour necrosis factor‐α agents was associated with an increased risk (adjusted odds ratio = 3.0; 95% confidence interval, 1.5–5.7). Approximately 50% of patients required additional therapy or new hospitalisation within 5 years due to a recurrent flare. Death occurred in three patients (0.9%).ConclusionsPatients with acute severe ulcerative colitis avoiding early colectomy are at risk of long‐term colectomy, especially if previously exposed to antitumour necrosis factor‐α agents or if rescue therapy during the acute attack was required because of steroid refractoriness.

Use of Anti-Tumour Necrosis Factor-Alpha Agents in the Management of HLA-B-27-Associated Uveitis: The First Case Series from India

ABSTRACT Purpose: The aim of this study was to evaluate the efficacy of adalimumab (ADL) and golimumab (GLM) in patients with HLA-B-27-associated uveitis. Method: We conducted a retrospective analysis of patients with HLA-B-27-associated uveitis who had received subcutaneous GLM and ADL between 2014 and 2018. Results: The study included 14 patients, 12 of whom received subcutaneous ADL and two patients were treated with subcutaneous GLM. Median age of the patients was 31.5 years (range 17–53 years). The most common associated systemic disease in these patients was ankylosing spondylitis (92.8%). Majority of the patients had anterior uveitis (71.4%) followed by anterior uveitis and intermediate uveitis (28.6%). Conclusion: ADL/GLM is a useful therapeutic option in refractory cases of HLA-B-27-associated uveitis, especially in patients with associated systemic manifestations.

Pregnancy outcomes in partners of male ankylosing spondylitis patients treated with anti-tumour necrosis factor-α biologics: real-life results from a single-centre cross-sectional study.

Most patients with inflammatory arthritis are at their reproductive ages. Use of anti-tumour necrosis factor alpha (anti-TNF-α) agents, one of the important treatment options for inflammatory arthritis, can cause foetal morbidity and mortality. While most studies on the effects of anti-TNF-α agents on pregnancy outcomes are about maternal exposure, the number of studies on the risks related to paternal exposure is insufficient. This study aimed to assess pregnancy periods and outcomes of the partners of male ankylosing spondylitis (AS) patients receiving anti-TNF-α treatment during the preconception period. Totally, 163 male AS patients using anti-TNF-α agents were identified from the Hacettepe University Biological Registry. Of these patients, 45 (27.6%) who declared that their partners got pregnant after initiation on anti-TNF-α agents were included. Data regarding demographics and drug exposure and pregnancy and infant outcomes were evaluated. Of 45 pregnancies, 39 (86.7%) resulted in healthy live births, 3 (6.7%) resulted in spontaneous abortion, and 3 (6.7%) were terminated with curettage. Of 39 live births, 34 (87.2%) were term and 5 (12.8%) were preterm, 30 (76.9%) had normal birth weight, 6 (15.4%) had low birth weight, and 3 (7.7%) had fetal macrosomia. No congenital malformations related to paternal exposure were observed. This study is valuable as being one of the studies providing pregnancy outcomes of partners of male AS patients receiving anti-TNF-α agents with its relatively high number of patients. The results suggested that paternal exposure to anti-TNF-α agents during preconception period could be safe on pregnancy outcomes.

Effects of preoperative anti‐tumour necrosis factor alpha infusion timing on postoperative surgical site infection in inflammatory bowel disease: A systematic review and meta‐analysis

Anti-tumour necrosis factor alpha agents (anti-TNF-α) have been widely used in patients with inflammatory bowel disease (IBD). However, few published meta-analyses have focused on timing of the last infusion before surgery. We evaluated the relationship between preoperative anti-TNF-α timing and postoperative surgical site infection to provide additional evidence for surgeons to choose appropriate dates for surgery. We searched from inception until January 2019 for studies that documented postoperative complications of adults with IBD who underwent preoperative anti-TNF-α treatment. Primary outcomes of included studies were the odds ratios of preoperative anti-TNF-α time frames (4, 8 and 12 weeks). In addition, surgical site infection and its subtypes (anastomotic leakage, abscesses and wound infection) were analysed. Twenty-seven publications were included. No significant difference between anti-TNF-α and control cohorts was observed for most postoperative surgical site infections (or its subtypes) when the preoperative anti-TNF-α infusion time window was within 4, 8 or 12 weeks. Additionally, no significant difference in postoperative complications was observed between preoperative anti-TNF-α windows of within four weeks and more than four weeks. In terms of surgical site infection and its subtypes, anti-TNF-α may be safe for ulcerative colitis and Crohn's disease patients who receive their last infusion of anti-TNF-α more than four weeks before surgery. We also found no evidence that anti-TNF-α was a risk factor when administered within four weeks, with the exception of subgroup results from a single study. Stratified by time window, use of anti-TNF-α until surgery has the potential to become a more considered strategy in clinical practice.

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

The association between anti-tumour necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumour necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285,811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumour necrosis factor alpha agents exposed and anti-tumour necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR] = 1.43, 95% CI, 0.91-2.25; P = 0.116; random effects: risk ratio [RR] = 0.83, 95% CI, 0.47-1.48; P = 0.534). However, monotherapy of anti-tumour necrosis factor alpha agents [random effects: IRR = 1.65, 95% CI, 1.16-2.35; P = 0.006; random effects: RR = 1.00, 95% CI, 0.39-2.59; P = 0.996] or combination therapy [random effects: IRR = 3.36, 95% CI, 2.23-5.05; P < 0.001; random effects: RR = 1.90, 95% CI, 0.66-5.44; P = 0.233] can significantly increase the risk of lymphoma. Exposition of anti-tumour necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumour necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease.

Increased knowledge of pathways involved in the pathogenesis of IBD has led to the development of new treatment options for Crohn's disease (CD) and ulcerative colitis (UC). Two new biological agents have been recently approved for IBD: vedolizumab and ustekinumab. They have different therapeutic targets (α4 β7 integrin for vedolizumab and interleukin-12/23 pathways for ustekinumab) than the primary biological class, anti-tumour necrosis factor alpha (anti-TNF) agents. As the armamentarium for IBD increases in coming years, it will become important to understand factors associated with response in order to best position and personalise therapy. To summarise the current data on predictors of response to vedolizumab and ustekinumab in IBD patients. We conducted a comprehensive literature review. A PubMed search was performed using pre-defined key words and terms to identify relevant studies on predictors of response. Patients with severe disease (by clinical activity and inflammatory biomarkers), or prior anti-TNF exposure are less likely to respond to vedolizumab. Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD. Initial response seems to predict a better long-term maintenance in both therapies (P < 0.001). Contrary to anti-TNF therapies, immunogenicity appears to play less of a role in response. As the number of new biological therapies increase in IBD, identifying patients who are most likely to benefit from specific agents is of paramount importance to help best position IBD therapies.

New Trends in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disease of the gastrointestinal (GI) tract. In the past decade a shift in the treatment paradigm of IBD has ensued. The availability of drugs capable of inducing mucosal healing, combined with the recognition that IBD is not an intermittent disease, but rather a progressive one causing bowel damage and disability, led us to a more stringent strategy. Tailored therapy with more aggressive treatment in high-risk patients, treating beyond symptoms, intervening early before damage occurs, optimizing therapeutic regimens, and actively pursuing sustained remission and sustained control of inflammation are strategies that are slowly being incorporated in our clinical practice. Furthermore, new drugs targeting different immunological pathways, such as vedolizumab, have recently been approved and therefore more therapeutic resources for patients failing anti-tumour necrosis factor alpha (anti-TNFα) agents will be available.The future years look promising for IBD. Hopefully the new trends in IBD management, combined with new drugs, will make possible to change the course of disease and provide better therapy and quality of life for patients suffering from this disabling disease.

Infliximab and adalimumab are stable in whole blood clotted samples for seven days at room temperature.

The biologic anti-tumour necrosis factor alpha (anti-TNFα) agents infliximab and adalimumab are monoclonal antibodies with binding specificity to TNFα, which are used for the treatment of Crohn's disease. Clinical response is varied from complete with mucosal healing, to primary non-response, loss of response and adverse drug reactions. Measuring trough blood levels of infliximab and adalimumab may guide clinical management. The sample handling requirements for infliximab and adalimumab were previously unknown. The aim of this study was to determine the in vitro stability of infliximab and adalimumab in samples stored for up to seven days at room temperature. Samples were stored as clotted whole blood or serum at room temperature for up to seven days, before being frozen (-20℃) and analysed as a batch for either infliximab or adalimumab. No significant difference between the concentration of infliximab and adalimumab measured in samples stored as serum or whole blood for seven days at room temperature, as compared to baseline was found (t-test; infliximab: P = .35 [serum], P = .38 [whole blood]; adalimumab: P = .12 [serum], P = .49 [whole blood]). The stability of infliximab and adalimumab at room temperature for seven days allows samples to be posted direct from clinics and research centres to the analysing laboratory.

Cerebrovascular events in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents.

Cerebrovascular accidents [CVA] have rarely been reported in inflammatory bowel disease [IBD] patients treated with anti-tumour necrosis alpha [anti-TNF alpha] agents. Our aim here was to describe the clinical course of CVA in these patients. This was a European Crohn's and Colitis Organisation [ECCO] retrospective observational study, performed as part of the CONFER [COllaborative Network For Exceptionally Rare case reports] project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNF alpha agents. Clinical data were recorded in a standardised case report form and analysed for event association with anti-TNF alpha treatment. A total of 19 patients were identified from 16 centres: 14 had Crohn's disease, four ulcerative colitis and one IBD colitis unclassified [median age at diagnosis: 38.0 years, range: 18.6-62.5]. Patients received anti-TNF alpha for a median duration of 11.8 months [range: 0-62] at CVA onset; seven had previously been treated with at least one other anti-TNF alpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNF alpha was discontinued in 16/19 patients. However, recurrent CVA or neurological deterioration was not observed in any of the 11 patients who received anti-TNF alpha after CVA [eight resumed after temporary cessation, three continued without interruption] for a median follow-up of 39.8 months [range: 5.6-98.2]. These preliminary findings do not unequivocally indicate a causal role of anti-TNF alpha in CVA complicating IBD. Resuming or continuing anti-TNF alpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent.

The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis

BackgroundThe overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. MethodsHere we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. ResultsIn one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. ConclusionsThese two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment.

Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease.

Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown. To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD. After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17-2.36 and RR: 1.43, 95% CI: 1.17-1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51-2.09 and RR: 1.68, 95% CI: 1.46-1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21-7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients. All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.

What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails?

The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient's life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn's disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.