Anal High-risk Human Papillomavirus Infection, Squamous Intraepithelial Lesions, and Anal Cancer in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Ulcerative colitis [UC] and Crohn's disease [CD] can be associated with severe comorbidities, namely opportunistic infections and malignancies. We present the first systematic review and meta-analysis evaluating the burden of anal human papillomavirus disease in patients with UC and CD. METHODS: PubMed, Web of Science, and Scopus were searched until November 2022. Meta-analyses were performed using random effects models. The protocol was recorded at PROSPERO register with the number CRD42022356728. RESULTS: Six studies, including 78 711 patients with UC with a total follow-up of 518 969 person-years, described the anal cancer incidence rate. For anal cancer incidence rate in CD, six studies were selected, including 56 845 patients with a total follow-up of 671 899 person-years. The incidence of anal cancer was 10.2 [95% CI 4.3 - 23.7] per 100 000 person-years in UC and 7.7 [3.5 - 17.1] per 100 000 person-years in CD. A subgroup analysis of anal cancer in perianal CD, including 7105 patients, was calculated with incidence of 19.6 [12.2 - 31.6] per 100 000 person-years [three studies included]. Few studies described prevalence of anal cytological abnormalities [four studies including 349 patients] or high-risk human papillomavirus [three studies including 210 patients], with high heterogeneity. Prevalence of cytological abnormalities or high-risk human papillomavirus was not associated with pharmacological immunosuppression in the studies included. CONCLUSION: The incidence of anal cancer is higher in UC than in CD, with the exception of perianal CD. There are limited and heterogeneous data on anal high-risk human papillomavirus infection and squamous intraepithelial lesions prevalence in this population.

Obstetric Considerations in Pregnant Women with Crohn's Disease.

Crohn's disease affects many women of childbearing age. Fecundity rates are often lower than in the general population due to reduced fertility during active inflammation, effects of pelvic surgery or voluntary childlessness. Many women have concerns regarding the effects of pregnancy on their Crohn's, any potential effect of medication on the fetus, and passing on Crohn's disease to the offspring. International guidelines on reproduction for women with Crohn's disease provide evidence-based advice to patients and health care professionals. There is an increasing literature on the safety of advanced medication for Crohn's disease during pregnancy. This review article therefore focuses on obstetric considerations beyond medication safety. We provide information on fertility, factors affecting pregnancy and fetal outcomes, obstetric complications, factors influencing mode of delivery, management of intestinal stomas during pregnancy and general considerations around breast feeding.

Systematic review with network meta-analysis: Risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease.

BACKGROUND: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age. AIMS: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis. METHODS: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473). CONCLUSIONS: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Understanding anti-TNF treatment failure: does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn's disease?

BACKGROUND: During illness, adaptations of the hypothalamic-pituitary-thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with inflammatory bowel disease. AIM: To assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn's disease METHODS: Thyroid function tests were undertaken in stored serum from biologic-naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS). RESULTS: Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27-0.34] vs 0.32 [0.28-0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25-0.33] vs. 0.32 [0.29-0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.85, p = 0.009), but not non-remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54-0.61], sensitivity 0.62 [95% CI 0.41-0.74], and specificity 0.53 [95% CI 0.42-0.73]). CONCLUSIONS: Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti-TNF treatment at week 14, but not non-remission at week 54.

Risk stratifying gastric ulcers: development and validation of a scoring system.

Objective: Debate is ongoing regarding the need for universal endoscopic follow-up to ensure gastric ulcer healing. We aimed to assess the value of follow-up oesophago-gastro-duodenoscopies (OGDs) for gastric ulcer healing and stratify patients according to risk of malignancy by developing a risk score. Design/method: All patients in National Health Service (NHS) Lothian with an index OGD and a diagnosis of gastric ulcer between 1 January 2014 and 31 December 2018 were identified. Data were analysed with logistic regression to identify factors significantly associated with a diagnosis of cancer; a risk score was derived and externally validated. Results: 778 patients were identified and 60.3% (469/778) of patients had a follow-up OGD. 8.6% (66/778) of patients were diagnosed with cancer. No cases of cancer were found on follow-up OGD of a benign appearing ulcer with negative biopsies. Macroscopic suspicion of malignancy was present at index OGD in 100% (3/3) of those diagnosed with cancer on subsequent OGDs. Older age (p=0.014), increased ulcer size (p<0.001) and non-antral location (p=0.030) were significantly associated with malignancy. A risk score (area under the curve (AUC) 0.868, p<0.001, minimum score=0, maximum score=6) was derived from these variables. 78.0% of patients with malignant ulcers scored ≥3, only 15.8% with benign ulcers scored ≥3 (negative predictive value (NPV) 97.4%). External validation yielded an AUC of 0.862 (p<0.001) and NPV of 98.6%; 84.0% of those with malignant ulcers scored ≥3. Conclusion: Ulcers with a combination of macroscopically benign appearances, at least six negative biopsies and a low risk score do not necessarily need endoscopic follow-up.

A propensity score-matched, real-world comparison of ustekinumab vs vedolizumab as a second-line treatment for Crohn's disease. The Cross Pennine study II.

BACKGROUND: The optimal choice of biological agents after failure of anti-tumour-necrosis-factor-(TNF)α agent in Crohn's disease (CD) is yet to be defined. AIMS: To assess the effectiveness and safety of ustekinumab compared to vedolizumab as second-line treatment in CD patients who failed anti-TNFα therapy. METHODS: Retrospective analysis of clinical response and remission at 14 and 52 weeks to ustekinumab by physician global assessment (PGA). A propensity score-matched analysis with a cohort treated with vedolizumab was performed. RESULTS: Of 282 patients (mean age 40 ± 15, F:M ratio 1.7:1) treated with ustekinumab, clinical response or remission was reached by 200/282 patients (70.9%) at 14 weeks, and 162/259 patients (62.5%) at 52 weeks. Overall, 74 adverse events occurred, of which 26 were labelled as serious (8.3 per 100 person-year). After exclusion of patients without prior anti-TNFα exposure and patients previously exposed to vedolizumab or ustekinumab, we analysed 275/282 patients (97.5%) on ustekinumab and 118/135 patients (87.4%) on vedolizumab. Propensity score analysis revealed that at 14 weeks, patients treated with ustekinumab were 38% (95% CI 25%-50%; P < 0.001) more likely to achieve clinical remission, while at 52 weeks, the difference of 9% (95% CI -15% to 33%; P = 0.462) was not significant. CONCLUSIONS: Ustekinumab was effective and well tolerated in this real-world cohort. While ustekinumab proved more effective at 14-weeks, we found no statistically significant differences at 52 weeks compared to vedolizumab.

Screening for TB in Hospitalised Patients with Inflammatory Bowel Disease before Anti-TNF Therapy: Is QuantiFERON® Gold Testing Useful?

Background-Tumour necrosis factor alpha (TNFα) plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and in immunity to Mycobacterium tuberculosis. Patients should be tested for latent tuberculosis infection using interferon-gamma release assays (IGRA/QF) prior to anti-TNFα therapy. Indeterminate QF results can delay anti-TNFα therapy. We sought to investigate factors associated with indeterminate QF results. Method-Retrospective study of all IGRA tests requested for gastroenterology patients in 2017. We compared inpatients and outpatients and investigated factors potentially associated with QF usefulness (steroid exposure, C-reactive protein (CRP), hypoalbuminaemia, thrombophilia). Results-We included 286 outpatients and 74 inpatients with IBD. Significantly more inpatients had an indeterminate IGRA (52.7% vs. 3.14% in outpatients; p < 0.0001). Laboratory parameters reflecting inflammation (high CRP, low albumin, low haemoglobin and high platelets) were also associated with an indeterminate QF (p < 0.0001). Exposure to steroids was more common in patients with an indeterminate QF (p < 0.0001). A binary logistic regression analysis revealed inpatient status and steroid exposure to be independently predictive of an indeterminate QF (p < 0.0001). Conclusion-There is a high chance of indeterminate QF results in inpatients. QF testing should ideally be performed in the outpatient setting at diagnosis.

IBD in pregnancy: recent advances, practical management.

Inflammatory bowel disease (IBD) poses complex issues in pregnancy, but with high-quality care excellent pregnancy outcomes are achievable. In this article, we review the current evidence and recommendations for pregnant women with IBD and aim to provide guidance for clinicians involved in their care. Many women with IBD have poor knowledge about pregnancy-related issues and a substantial minority remains voluntarily childless. Active IBD is associated with an increased risk of preterm birth, low for gestation weight and fetal loss. With the exception of methotrexate and tofacitinib the risk of a flare outweighs the risk of IBD medication and maintenance of remission from IBD should be the main of care. Most women with IBD will experience a normal pregnancy and can have a vaginal delivery. Active perianal Crohn's disease is an absolute and ileal pouch surgery a relative indication for a caesarean section. Breast feeding is beneficial to the infant and the risk from most IBD medications is negligible.

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Patients' perception of colonoscopy and acceptance of colonoscopy based IBD related colorectal cancer surveillance.

OBJECTIVES: Patients with Inflammatory Bowel Disease (IBD) are at an increased risk of colorectal cancer (CRC). Current surveillance for CRC involves often uncomfortable colonoscopy. To assess IBD patients' perception of colonoscopy and examine preferences for hypothetical alternatives. METHODS: IBD patients in clinical remission rated acceptable frequency of colonoscopy and hypothetical alternatives to colonoscopy-based surveillance (preference of yearly blood, yearly stool or 5-yearly imaging tests over 5-yearly colonoscopy). Participants rated discomfort of the last colonoscopy was compared with hospital records. RESULTS: Of 282 patients with recollection of colonoscopy 65.8% rated the discomfort as moderate to severe, which correlated weakly with endoscopists' perception (r = 0.225; p = 0.015). There were no significant differences in patients' or endoscopists' perceptions of discomfort between sedated and unsedated colonoscopies. Undergoing a yearly colonoscopy was acceptable to 49.5%. Experienced discomfort did not correlate with patients' views on acceptable frequency of surveillance colonoscopy. Over 95% of patients would prefer blood, stool, or imaging tests over colonoscopy but nearly half expected sensitivities ≥95%. CONCLUSION: A large proportion of IBD patients experienced colonoscopy as moderate to severely uncomfortable but would still accept colonoscopy surveillance frequency according to current guidance. Participants expected sensitivities ≥95% for potential alternatives to colonoscopy-based surveillance programs. EXPERT OPINION: IBD patients frequently experience colonoscopy as uncomfortable but accept colonoscopy as the gold standard for colorectal cancer surveillance. The currently suggested frequencies of surveillance by colonoscopy are acceptable to IBD patients. They do however express a clear preference for non-invasive surveillance techniques. Some promising initial results have been obtained based on faecal or blood sampling. However, these have yet to be tested in large prospective studies to determine their sensitivity and specificity. IBD patients expect these non-invasive tests to meet high standards for sensitivity. In our view it is feasible that analogue to faecal immunochemistry based testing for general population bowel cancer screening non-invasive IBD surveillance techniques will emerge. This could lead to a reduction in the need for colonoscopy to those testing positive on faecal or blood based surveillance.

The Association of Introducing a Faecal Calprotectin Testing Pathway for Suspected Inflammatory Bowel Disease in Primary Care and Time to Diagnosis or Treatment.

BACKGROUND: Primary care faecal calprotectin (FC) was introduced in Leeds in 2014 to distinguish inflammatory bowel disease (IBD) from irritable bowel syndrome and with the hope that it may reduce time to IBD diagnosis and treatment. This study examines the association of FC with referral routes, time to diagnosis, and time to treatment. METHODS: All patients newly referred to IBD clinics in 2013 and 2016 were studied. Data on referral routes and dates, FC, date of first treatment, and proxy outcomes for disease severity were collected. RESULTS: In 248 patients, there were no differences between 2013 and 2016 cohorts regarding baseline data and disease severity. The number of direct referrals to gastroenterology rose from 3% (2013) to 17% (2016), whilst 10% were diagnosed during emergency admissions. Referrals via suspected cancer pathways remained high (38% in 2013, 28% in 2016), whilst many had initial investigations at independent centres (16% in 2013, 24% in 2016). Time from referral to diagnosis was similar between 2013 (0.77 month) and 2016 (1.10 months, p = 0.2). A total of 48 (33.3%) patients had FC checked prior to referral, and 37.5% of these were referred directly to gastroenterology. Time from diagnosis to treatment reduced from 1.37 months (2013) to 0.72 month (2016, p = 0.01). CONCLUSION: Patients present via a multitude of referral pathways, but FC was associated with increased direct referrals to gastroenterology. We found a variation in time to diagnosis and treatment depending on referral routes. Further work is required to ensure patients with suspected IBD get referred to IBD services in a timely manner.

Stigmatisation and resilience in inflammatory bowel disease.

Inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis, is an immune-mediated, chronic relapsing disorder characterised by severe gastrointestinal symptoms that dramatically impair patients' quality of life, affecting psychological, physical, sexual, and social functions. As a consequence, patients suffering from this condition may perceive social stigmatisation, which is the identification of negative attributes that distinguish a person as different and worthy of separation from the group. Stigmatisation has been widely studied in different chronic conditions, especially in mental illnesses and HIV-infected patients. There is a growing interest also for patients with inflammatory bowel disease, in which the possibility of disease flare and surgery-related issues seem to be the most important factors determining stigmatisation. Conversely, resilience represents the quality that allows one to adopt a positive attitude and good adjustments despite adverse life events. Likewise, resilience has been studied in different populations, age groups, and chronic conditions, especially mental illnesses and cancer, but little is known about this issue in patients with inflammatory bowel disease, even if this could be an interesting area of research. Resilience can be strengthened through dedicated interventions that could potentially improve the ability to cope with the disease. In this paper, we focus on the current knowledge of stigmatisation and resilience in patients with inflammatory bowel disease.

Assessment of steroid use as a key performance indicator in inflammatory bowel disease-analysis of data from 2385 UK patients.

BACKGROUND: Patients with IBD are at risk of excess corticosteroids. AIMS: To assess steroid excess in a large IBD cohort and test associations with quality improvement and prescribing. METHODS: Steroid exposure was recorded for outpatients attending 19 centres and associated factors analysed. Measures taken to avoid excess were assessed. RESULTS: Of 2385 patients, 28% received steroids in the preceding 12 months. 14.8% had steroid excess or dependency. Steroid use was significantly lower at 'intervention centres' which participated in a quality improvement programme (exposure: 23.8% vs 31.0%, P < .001; excess 11.5% vs 17.1%, P < .001). At intervention centres, steroid use fell from 2015 to 2017 (steroid exposure 30.0%-23.8%, P = .003; steroid excess 13.8%-11.5%, P = .17). Steroid excess was judged avoidable in 50.7%. Factors independently associated with reduced steroid excess in Crohn's disease included maintenance with anti-TNF agents (OR 0.61 [95% CI 0.24-0.95]), treatment in a centre with a multi-disciplinary team (OR 0.54 [95% CI 0.20-0.86]) and treatment at an intervention centre (OR 0.72 [95% CI 0.46-0.97]). Treatment with 5-ASA in CD was associated with higher rates of steroid excess (OR 1.72 [95% CI 1.24-2.09]). In ulcerative colitis (UC), thiopurine monotherapy was associated with steroid excess (OR 1.97 [95% CI 1.19-3.01]) and treatment at an intervention centre with less steroid excess (OR 0.72 [95% CI 0.45-0.95]). CONCLUSIONS: This study validates steroid assessment as a meaningful quality measure and provides a benchmark for this performance indicator in a large cohort. A programme of quality improvement was associated with lower steroid use.

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.

BACKGROUND: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. METHODS: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. FINDINGS: We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004). INTERPRETATION: Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes. FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion.

Comorbidities Rather Than Age Are Associated With the Use of Immunomodulators in Elderly-onset Inflammatory Bowel Disease.

BACKGROUND AND AIM: The use of immunomodulators (IMs) is often avoided in elderly patients with inflammatory bowel disease (IBD) due to concerns about complications. Our aim is to compare the use of IMs in elderly and younger patients with Crohn's disease (CD) or ulcerative colitis (UC) and identify markers that predict their use. METHODS: In this retrospective cohort study, patients diagnosed with IBD from 1970 to 2009 were recruited from the "Sydney IBD Cohort." Patients diagnosed at age 60 years old or older and between 16 and old 40 years were classified as "elderly-onset" and "young-onset" respectively. RESULTS: A total of 255 elderly-onset patients (115 CD, 140 UC) and 1244 young-onset patients (657 CD, 587 UC) were recruited. Most elderly-onset patients had colonic CD (61.4%), whereas young-onset patients had predominantly ileocolonic CD (42.8%, P < 0.0001). Left-sided UC was the most common disease localization for both elderly-onset (52.1%) and young-onset patients (42.2%, P = 0.013). The cumulative probability of IM exposure at 5 years post-diagnosis was significantly less in elderly-onset patients compared with young-onset patients for CD (20.0% vs 33.4%, P = 0.0002) and UC (7.8% vs 13.4%, P = 0.0007). Age at diagnosis was not associated with the time to IMs introduction. Charlson Comorbidity Index was shown to delay IM introduction in CD (hazard ratio [HR] 0.863; 95% CI, 0.787-0.946; P = 0.002) and UC (HR 0.807; 95% CI, 0.711-0.917; P = 0.001). Early IM use was associated with reduced need for abdominal and perianal surgery in CD (HR 0.177; 95% CI, 0.089-0.351; P < 0.0001). CONCLUSIONS: Comorbidity and not age at diagnosis is associated with IM introduction. Early IM is associated with reduced surgery in both young- and elderly-onset CD but not UC.