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IntroductionMetastatic Crohn’s disease (MCD), also known as cutaneous Crohn’s disease is one of the rarest cutaneous lesions in IBD. It is defined by granulomatous lesions infiltrating the skin that are discontinuous from the affected GI tract. In most occasions, MCD occurs parallel to the course of a well-establish GI disease, but occasionally it can precede the GI manifestations from months to years. Studies addressing the therapeutic approach to MCD are limited. Ustekinumab is licenced for Crohn`s disease and also for skin disorders including psoriasis. We report our experience in managing MCD in a tertiary IBD centreMethodsThis is a single centre retrospective review of biopsy proven cutaneous Crohn’s disease. Patient details obtained from patient records included demographic data, previous failure to biologics and/or IMS, response and time to response to Ustekinumab and therapeutic drug monitoring.ResultsA retrospective review of patients with cutaneous Crohn’s disease was performed. All patients had undergone a skin biopsy for histologically confirmation. Ten patients were included (Males: Females 5:5). Median age was 53 years (IQR 24–67). The most common location was the perianal area often preceded by a surgical wound from a proctectomy and 2 patients had peristomal skin affected. Ninety- percent of patients had failed antiTNF therapy and 6 out of 10 had failed to both Infliximab and Adalimumab, one of them had also lost response to Vedolizumab. All patients received ustekinumab with median follow up since initiation of 45 months (IQR 27–60). All patients noticed improvement since initiation of Ustekinumab with a median time to response of 10 weeks (IQR 4–28). Four out of 10 patients achieved a complete healing of the skin lesions (see example picture shared with patient’s consent) while rest of patients reported a partial response. Most patients had therapeutic or supratherapeutic Ustekinumab level ranging from 2 to 6 mg/L. Dose escalation was done in 8 patients.Abstract P68 Figure 1ConclusionsMetastatic Crohn’s disease is a rather uncommon entity with different clinical manifestations. Our series report satisfactory response to ustekinumab in MCD. Larger studies are required to confirm these findings.

BackgroundThere is emerging data on the continued efficacy of infliximab when switched from intravenous (IV) to subcutaneous (SC) route in Inflammatory bowel disease (IBD). The impact of cessation of concomitant immunomodulators (IMMs) following switch on trough levels or development of anti-drug antibodies (ADAs) is not evaluated in real world practice. We aimed to study the impact of cessation of IMMs following switch of infliximab from IV to SC route and determine relationship with HLA- DQA1 *05 status.MethodsConsecutive patients who participated in a planned switch programme were prospectively included. Clinical, biomarker and pharmacokinetic data were collected pre-switch, and at 8 weekly intervals post switch for 6 months. Trough levels and remission status in patients who discontinued or reduced the dose of IMMs were compared with those who remained or continued same dose on IMMs. All patients had HLA-DQA1*05 status determined at initiation of Infliximab and we evaluated the impact of HLA status on development of anti-Infliximab antibodies post switch.ResultsOne hundred and fifteen patients (M: F=1.4:1, Median age 44 years (13-76), UC/CD (48/67) who completed 6 month follow up were included. All patients were in clinical and biomarker remission prior to the switch. 72 patients (62.6%) were on concomitant IMMs and 46 (40.86%) was HLADQA1*05 positive. The mean infliximab trough level prior to switch was 5.54 µg/mL which increased 8 weeks post switch to 12.52 µg/mL (p=0.006). The enhancement of levels persisted at 16 weeks (Mean 16.28) and at week 24 (17.25). 36 patients (32%) were positive for ADAs before switch; in 8 patients (22%) the ADAs disappeared at 8 weeks and in further 4 (total 33%) by 6 months. In total antibody titre reduced or become negative in 17 patients (48.6%), static in 14 patients (40%) but increased in 5 patients (14%) without significant lowering of trough levels. 18 of the 72 patients (25%) had IMMs discontinued, and dose reduced in further 21 patients. The total de-escalation rate was 54% and none of these patients developed ADAs at 6 months irrespective of the HLADQA1*05 status (HR = 0.76, 95% = 0.64 to 1.73, p 0.12). One patient switched back to IV due to personal preference. At 6 months none of the patients discontinued SC infliximab or were switched within or out of class.Abstract O40 Figure 1ConclusionsSwitch from IV to SC infliximab is effective in maintaining and enhancing trough levels with positive impact on reducing ADAs. It is feasible to de-escalate concomitant IMMs in a considerable proportion of patients following switch. Economic analysis of switch should be incorporated in the feasibility of IMMs withdrawal.

BackgroundInformed choice about treatment options in the setting of Acute Severe Ulcerative Colitis (ASUC) is often challenging for the patient due to state of heightened stress in this acute setting and the ongoing uncertainties about treatment outcomes, it is uncertain whether patients reconcile with their choice made in this acute setting. We aimed to evaluate decisional conflict and decisional regret among ASUC patients and examine whether decisional conflict contributed to regret.MethodsPatients included in a prospective observational study of ASUC filled two psychometric instruments Decisional Conflict Scale (DCS) and Decisional Regret Scale (DRS). Patients were followed up for 12 months. Differences in DCS scores between patients who underwent colectomy versus those treated with medical therapy were evaluated. Changes in DRS scores at follow up was analysed and factors resulting in high decisional regret scores were evaluated.ResultsOf the 219 patients admitted with ASUC 87 completed the DRS at 12 months. Of these, 70 had no regrets about their treatment, 11 were neutral, and 6 regretted their decision figure 1.Among patients who underwent colectomy, 12 patients completed the DCS at 90 days, with 8 agreeing that it was the right decision by 12 months.For biologic treatment, 70 patients completed the DCS at 90 days, with 63 agreeing it was the right choice, and 44 patients completed the DCS at 12 months, with 43 agreeing. A subgroup of 36 patients who were unsure about their treatment choice at 90 days showed a more divided response, with 17 agreeing it was the right choice by 12 months, while 11 remained uncertain.Abstract P316 Figure 1ConclusionThis study highlights the psychological challenges faced by ASUC patients in their treatment decisions. Decisional conflict is highly prevalent, particularly among those uncertain about their treatment options. These findings suggest the need for developing tailored decision aid tools to facilitate improved shared decision-making processes in ASUC.

ObjectiveAntitumour 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.DesignAntibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 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.ResultsRates 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).ConclusionsInfliximab 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.

IntroductionCombination therapy using thiopurines or methotrexate is recommended to reduce the risk of immunogenicity in IBD patients treated with anti TNF agents. The PANTS study reported the association of HLA DQA1*05 carriage with development of anti-drug antibodies to anti TNFs in patients with Crohn`s disease. Since 2020, we have incorporated determination of HLA status in the pre-biologic screening of IBD patients. We aimed to evaluate persistence at 6 and 12 months in patients stratified to receive mono or combo therapy with anti TNFsMethodsA prospective database of all IBD patients starting biologics was interrogated to select patients initiating on anti TNF agents. We excluded patients Crohn`s disease perianal fistula who had specific indication for combo therapy, patients with acute severe UC receiving accelerated induction those who were already on imunomodulators prior to initiation of anti TNF agents. Data was collected on demographics, disease characteristics, HLA DQA1*05 status, drugs levels and antidrug antibody status at week 6, week 14 and at least one time point during a 1 year maintenance period. The primary outcome was drug persistence at 12 months.ResultsOne hundred and fifty six patients were initiated on anti TNFs during the study period. HLA DQA1*05 was positive in 59 (37.8%) of patients. These patients received combination therapy (Infliximab + thiopurines in 42, Infliximab plus methotrexate in 9, adalimumab plus azathioprine 6, Adalimumab plus methotrexate in 2). All patients negative for HLADQA1805 received monotherapy with infliximab (78) or adalimumab (19). Primary non response was identified in 30 patients (overall 19%, Monotherapy 17(17.5%), combo therapy 13 (22% ) and were switched to a non anti TNF agent Further 9% of patients had dose escalation due to suboptimal drug levels and partial response among whom 6 patients were switched to another class. Eleven patients stopped anti TNFs (4 and 7 in mono and combo therapy group respectively) due to intolerance and five patients discontinued immunomodulators in the combo therapy due to adverse effects.Anti-drug antibodies was detected at week 6 in 2 patients in the monotherapy group and 3 patients in combo therapy group (p=NS). There was no difference in rates of antidrug antibody development during maintenance period between the two groups. One hundred and twelve patients remained on anti TNFs across both groups at 12 months follow up. The overall drug persistence rates was similar in the mono and combination therapy group (66.1% vs 72.2%, p=NS).ConclusionsHLA DQA1*05 status incorporated anti TNF treatment strategy may alleviate the need for combination therapy in IBD patients with no impact on development of anti-drug antibodies and drug persistence. A biomarker stratified randomised trial is recommended.

IntroductionThe genetic variation HLA-DQA1*05 has been reported to be associated with anti-Infliximab antibody in CD. The relevance in UC patients receiving infliximab is uncertain.AimTo evaluate the association of HLA-DQA1*05 and infliximab antibody formation, treatment changes and infliximab persistence in a real world setting of single centre cohortMethodsInfliximab treated UC patients (n=94) were retrospectively screened for HLA-DQA1*05. The risk of anti-infliximab antibody formation, absent drug levels in presence of antibody, change in therapy from infliximab were assessed in variant carrying patients in comparison to those without the variants. The proportion of patients needing dose optimisation of infliximab also evaluated.ResultsAnti-infliximab antibodies were detected in 41.5% of patients in a median follow up of 14.75 (IQR 9-29) months. HLA-DQAI*05 was positive in 39.13% of patients. 52.2% of patients were on concomitant immunomodulators. Higher proportion of patients with HLA-DQA1*05 developed anti-Infliximab antibodies (59% Vs 24%, p=0.002). Eighty percent of patients who had anti Infliximab antibodies with absent drug levels were positive for HLA-DQA1*05 with Hazzard Ratio (HR) for development of anti-Infliximab antibodies of 4.54 (95% CI 1.73-11.89) and for antibodies with absent infliximab drug levels 9.86 (95% CI 2.43 -40.01). Higher proportion of HLA-DQA1*05 patients required dose escalation (78% vs 31%, p=0.001). After adjusting for age, initial infliximab dose and concomitant immunomodulator use, there was no difference anti TNF persistence in patients with HLA-DQA1*05 variant (HR 2.36, 95% CI 0.89-6.25, p=0.06).Abstract HMO-5 Figure 1Antibody formation in infliximab treated patientsAbstract HMO-5 Figure 2Infliximab persistenceConclusionsDetermination of HLA-DQA1*05 status may identify patients at higher risk of anti-infliximab antibodies in ulcerative colitis. Early intervention with dose optimisation and concomitant immunomodulation may avoid loss of response and facilitate treatment persistence.

IntroductionThe PANTS study reported high risk of immunogenicity and loss of response in anti Tumor Necrosis Factor (anti-TNFs) treated Crohn’s disease (CD) patients carrying HLADQA1*05 allele. The proposed biomarker stratified trial to evaluate the usefulness of HLA testing prior to initiation of anti-TNFs is not yet available.AimTo evaluate the use of HLADQA1*05 as part of pre-biologic screening in IBD patients initiating biologics on MDT decision on drug choice and disease outcomesMethodsWe prospectively included all IBD patients who had HLADQA1*05 tested prior to initiation of biologics over a period of 12 months. Patients with definitive indication for one class of drug or drug strategy (perianal fistula, acute severe colitis, contraindications to infliximab, co-existent EIMs) were excluded. Primary outcome was treatment persistence at 6 and 12 months. Secondary outcomes were steroid free remission at 6 and 12 months, use concomitant immunosuppression and proportion needing dose escalation.ResultsSeventy-six patients were included in analysis (UC= 32, CD=43, IBD-U =1). HLADQA1*05 was positive in 46.7% of patients. The therapy class choice was as recorded in figure 1. Concomitant immunosuppression was used in 44% of the whole cohort and in 100% of HLADQA1*05 positive patients started on anti-TNF agents. Primary non-response was recorded in 8 patients and secondary loss of response in 3 patients. Among patients started on anti-TNFs, anti-drug antibodies were detected in 10 (15.6%) patients with 7 out of 10 positive for HLADQA1*05. However, only 3 (4.6%) had undetectable drug levels in the presence of antibody and all three were HLADQA1*05 positive. Two patients had reactions during induction therapy both were HLADQA1*05 positive and were on combination therapy with Infliximab. Therapy persistence with initial drug strategy and steroid free remission at 6 months was recorded in 77.1% and 78% respectively. There was no significant difference in drug persistence rates at 6 months and 12 months in patients with HLADQA1*05 variant or those with variant absent (Figure 2). Steroid free remission at 6 and 12 months was also similar irrespective of the variant status (Figure 3)Abstract PMO-41 Figure 1Initial Theraphy choiceAbstract PMO-41 Figure 2Treatment presistance with initial theraphy strategyAbstract PMO-41 Figure 3Steroid free remissionConclusionsChoice of therapy incorporating HLADQA1*05 status may allow anti-TNF monotherapy and tailoring of therapy in IBD patients. A randomised stratified biomarker trial is required to determine the utility of pre-treatment testing.

IntroductionThe efficacy of ustekinumab in prior biologic exposed refractory patients with inflammatory bowel disease is significantly inferior to those who are bio naïve. The optimal therapeutic level and hence the optimal dosing strategy in this setting is uncertain. Whether early dose optimisation is beneficial in this group of patients has not been evaluated. We aimed to compare the effectiveness and safety of early dose optimisation for maintenance compared to conventional maintenance regime in a retrospective cohort of refractory IBD patients.MethodsAll patients initiated on ustekinumab following failure of one or more anti-TNF agents were included. Patients who received conventional maintenance regime (Q8W) was compared to those who received accelerated maintenance regime (Q4H). The primary end point was steroid free remission at 12 months or at last follow up. The secondary end points were ustekinumab persistence at 6 months and 12 months, need for surgery and drug related infectious or non-infectious complications.ResultsOne hundred and four patients were included (male: female 48:56). Median follow up was 11 months (IQR 5-14). Fifty-six patients received accelerated dosing regimen while 48 patients received standard dosing regime. Dose escalation was required in 18 patients (37.5%) of standard dosing regimen while four patients (7.1%) in the accelerated dosing regimen had dose de-escalation. Higher proportion patients in the accelerated dosing regimen were in steroid free remission 87.5% vs 68.8% (p=0.018). Proportion of patients requiring surgery was higher in the standard dosing regimen group (22.91 5 vs 7.14%, p = 0.02). Ustekinumab persistence in patient started on the accelerated regime and conventional dosing regime was not significantly different at 6 months (94.1% and 95.3%, p=0.58) and 12 months (84.4% and 95.3, p=0.1). No serious drug related complications observed in either group.ConclusionsEarly dose optimisation of Ustekinumab improves steroid free remission rates and reduces the need for surgery in patients with anti-TNF refractory patients with IBD.

Healthcare organisations have had to make adaptations to reduce the impact of the Coronavirus 2019 (COVID-19) pandemic. This has necessitated urgent reconfiguration within inflammatory bowel disease (IBD) services to ensure safety of patients and staff and seamless continuity of care provision. To describe the adaptations made by a large inflammatory bowel disease service, caring for over 3,500 IBD patients, in response to the COVID-19 pandemic. A diary record of responses to the pandemic were logged, and meeting minutes were reviewed. Data were recorded from IBD advice lines, multidisciplinary team (MDT) meeting minutes, infusion unit attendances, and electronic referral systems for the 8-week period from 9 March 2020 until 2 May 2020. Descriptive analysis was performed. The IBD service at Hull University Teaching Hospitals NHS Trust (IBD Hull) instituted rapid structural and functional changes to the service. Outpatient services were suspended and substituted by virtual consultations, and inpatient services were reduced and moved to ambulatory care where possible. The delivery of biologic and immunomodulatory therapies was significantly modified to ensure patient and staff safety. There was a substantial increase in IBD advice line calls. The rapidly evolving COVID-19 pandemic required a prompt response, regular reassessment and planning, and continues to do so. We share our experience in of the successful adaptations made to our IBD service.

Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts.