Initiation Of Infliximab Research Articles

S2424 Infliximab-Induced Acute Liver Failure in a Patient With Crohn’s Disease Requiring Orthotopic Liver Transplantation

INTRODUCTION: Among a plethora of adverse effects attributable to drugs of the TNF-α class, hepatotoxicity is rarely cited. We present the case of a patient with Crohn’s disease (CD) who was started on infliximab and subsequently developed acute liver failure (ALF) necessitating transplant. CASE DESCRIPTION/METHODS: A 25-year-old male with ileocolonic and perianal CD was started on infliximab and methotrexate. Two months later, he reported anorexia and weight loss after which methotrexate was discontinued. Three months after infliximab initiation, he developed acute onset pruritus, pale stools, and dark urine. Physical exam was remarkable for scleral icterus and jaundice without asterixis. At the time, total bilirubin was 10.7 mg/dL, International Normalized Ratio (INR) was 1.6, alkaline phosphatase (ALP) was 257 IU/L, aspartate aminotransferase (AST) was 2776 IU/L, and alanine transaminase (ALT) was 499 IU/L. The patient underwent evaluation for acute liver disease. Infectious serologies were negative. Ultrasound of the liver with Doppler studies was unremarkable for hepatic vasculature thrombosis. A liver biopsy demonstrated acute on chronic hepatitis with extensive hepatocellular necrosis (Figures 1 and 2). Given predominance of plasma cells along with mildly positive ANA and ASMA and exclusion of other potential etiologies, autoimmune hepatitis (AIH) induced by infliximab was likely. Empiric methylprednisolone was initiated. However, the patient’s clinical course deteriorated and he progressed into ALF. He then underwent successful transplantation. DISCUSSION: ALF secondary to infliximab has been reported in the literature at a greater frequency compared to other drugs of the TNF-α class. The mechanism of action likely involves development of AIH, characterized by typical clinical history, laboratory findings, and distortions in histological architecture. The prevalence and timeline for the development of hepatotoxicity has not been established. The mainstay of treatment involves steroid therapy, and if this fails, then liver transplantation must be considered. Although methotrexate has also been reported to cause hepatotoxicity, infliximab was considered to be etiology for AIH given the significantly longer half-life of infliximab and the more acute nature of hepatotoxicity. Patients must avoid anti-TNF-α therapy for life to prevent recurrence of ALF. Further studies are needed to risk stratify CD patients for development of ALF.Figure 1.: Massive hepatocellular necrosis with infiltration of portal lymphocytic and lymphoplasmacytic cells.Figure 2.: Acute hepatitis with massive hepatocellular necrosis.

O08 Neurosarcoidosis mimicking CNS lymphoma

Case report - IntroductionSarcoidosis is a multisystem disease which involves formation of inflammatory lesions known as granulomas. Central nervous system’s involvement is rare. Clinical neurologic complications occur in approximately 5% of patients.Diagnostic criteria for neurosarcoidosis in the absence of central nervous system (CNS) histology are not firmly established. A clinically compatible picture, exclusion of other neurological diseases, and histological confirmation of disease elsewhere are generally required. We present a case report of neurosarcoidosis presenting as a lymphoma mimic. Case report - Case descriptionA 45-year-old right-handed white male with past medical history of obstructive sleep apnoea, presented to the acute neurology clinic with several weeks’ history of cognitive decline and severe L facial pain. He had lost 2 stone in weight and there was loss of appetite over 2 months. Neurology examination (including cranial nerves) was unremarkable except for a mini mental state score of 25/30, where he lost points on the attention and recall tasks. CT head revealed a mass in the L cavernous sinus. Brain MRI with contrast revealed an enhancing lesion in the left. suspicious of lymphoma. Additional work up included whole body FDG-PET/CT scan, lumbar puncture. Lumbar puncture showed normal CSF. Serum ACE was normal and a paraneoplastic panel. Whole body PET/CT scan showed FDG avid areas in the bilateral neck, axillary regions, chest and pelvis and inguinal regions, highly consistent with lymphoma. Bone marrow biopsy was negative for lymphoma. Further EBUS biopsy before start of prednisolone revealed multiple non caseating granulomas, diagnostic of sarcoidosis. The patient was treated with oral prednisolone, followed by anti-tumour necrosis factor-a infliximab infusion.A repeat brain MRI with contrast done at five months after initiation of steroids, methotrexate and infliximab showed complete resolution of the intracranial lesion. Neurological and neuropsychological evaluation three months after diagnosis demonstrated resolution of facial pain and cognitive decline. Case report - DiscussionThere exists several mimics of neurosarcoidosis. Both clinically and radiographically, neurosarcoidosis can be difficult to diagnose. MRI and PET scan in neurosarcoidosis can often mimic malignancy. Early symptomatic treatment is advised for neurosarcoidosis, thus there is a clear need for more prompt diagnosis to allow commencement of the appropriate therapy. There is no known cure for neurosarcoidosis. Immunosuppression is the primary means of controlling the disease, and corticosteroids are the cornerstone of therapy. Treatment options are limited; however, there is more evidence suggesting that steroids and immunomodulatory agents such as infliximab may improve clinical outcomes, which may be due to the anti-TNF-α effect on reducing oxidative stress. Case report - Key learning pointsOur patient had a clinical presentation suspicious of lymphoma, however he did not have lymphoma and had a good response to corticosteroids and infliximab. Often, FDG PET/CT scan can be misleading and may appear to be neoplastic rather than inflammatory. ACE levels in both CSF and serum are not always positive. Biopsy in these cases is necessary to establish correct diagnosis. Prompt treatment can lead to significant reduction in mortality and morbidity

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy.

The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

Efficacy of Granulocyte and Monocyte Adsorptive Apheresis in Patients With Inflammatory Bowel Disease Showing Lost Response to Infliximab

In inflammatory bowel disease [IBD] patients, antibody-to-infliximab [ATI] generation is responsible for loss of response [LOR] and infusion reaction [IR] to infliximab. An immuno-therapeutic approach is considered an option to overcome LOR. Granulocyte/monocyte adsorptive apheresis [GMA] using an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects in IBD patients. We developed an ATI-CAI assay utilizing a C1q immobilized plate and applied it to measure ATI in patients who were receiving infliximab, including 56 with sustained response, 76 with LOR and six with IR. Furthermore, 14 patients with LOR and two with paradoxical skin reactions who received infliximab + GMA combination therapy were analysed. Fourteen patients with LOR, seven with Crohn's disease and seven with ulcerative colitis, showed significantly improved clinical indices [p = 0.0009], and decreased ATI [p = 0.0171] and interleukin-6 [p = 0.0537] levels at week 8 following initiation of infliximab + GMA therapy. Nine patients who received combination therapy achieved remission, which was maintained to week 24 with infliximab alone. Additionally, cutaneous lesions in two patients with IR were improved. ATI-CAI assay efficiency was not influenced by infliximab concentration during the test. Pre- and post-infliximab infusion ATI levels were not different. Patients with ATI greater than the 0.153 μg/mL cut-off value were likely to experience LOR [odds ratio 3.0]. Patients who received infliximab + GMA therapy appeared to regain clinical response to infliximab by a decrease in ATI level. Furthermore, the concentration of infliximab in the test did not influence ATI measurement, but was associated with clinical response.

A104 A STUDY OF POST-INDUCTION INFLIXIMAB TROUGH LEVELS DEMONSTRATES MOST PEDIATRIC IBD PATIENTS ARE BEING UNDERDOSED

Abstract Background Infliximab (IFX) is widely used for induction and maintenance of remission in pediatric inflammatory bowel disease (PIBD). Post induction IFX trough levels are a predictor of clinical and biochemical remission at week 52. Aims - evaluate the effectiveness of infliximab (IFX) induction regimens in attaining therapeutic post induction IFX trough levels in 2 PIBD cohorts. - investigate baseline laboratory values and patient factors as predictors of post-induction levels. Methods 78 patients from Vancouver, Canada [Cohort 1 (C1) originator IFX; variable dose induction regimen] and 62 patients from Glasgow, Scotland [Cohort 2 (C2) replication cohort - biosimilar IFX; standard induction of 5mg/kg at 0, 2 and 6 weeks, with 8 weekly maintenance] were included in the study. Baseline characteristics and laboratory values from time of IFX initiation were recorded. Mann-Whitney U Testing was utilized to analyse the relationship between IFX trough levels and lab parameters. Results The median pre-dose 4 trough in C1 &amp; C2 was 4.25mg/L (IQR 7.8) and 1.85mg/L (IQR 3.38) respectively. In C1 patients who had a trough level &amp;lt;3mg/L pre-dose 4, 62% (20/32) had already had a dose adjustment documented. The IFX dose of 50% (39/78) of C1 patients and 65% (40/62) of C2 patients was escalated following the pre-dose 4 IFX level. TABLE 1 Baseline median albumin (Alb) was significantly lower and replicated in both cohorts in those with low pre-dose 4 IFX levels: IFX trough &amp;lt;0.8mg/L C1: Alb 30g/L vs 37.5g/L in IFX ≥0.8mg/L, p=0.002 C2: Alb 34.5g/L vs 37g/L in IFX ≥0.8mg/L, p=0.02 IFX trough &amp;lt;3.0mg/L C1:Alb 34.5g/L vs 38g/L in IFX ≥3.0mg/L, p= 0.05 C2:Alb 35g/L vs 37g/L in IFX ≥3.0mg/L, p=0.04 IFX trough &amp;lt;5.0mg/L C1:Alb 35g/L vs 39g/L in IFX ≥5.0mg/L, p=0.006 C2:Alb 35g/L vs 37g/L in IFX ≥5.0mg/L, p=0.45 In the combined cohort (C1 + 2), patients with baseline albumin ≤30g/L had significantly lower IFX levels pre-dose 4 than those with albumin &amp;gt;30g/L (1.4mg/L vs 3.55mg/L, p=0.0003). In patients with an albumin ≤30g/L, 23% (6/26) achieved a dose 4 trough level of ≥3.0mg/L, however only 1/6 patients received a standard induction regime meaning only 4% (1/26) of patients had a trough ≥3.0mg/L on standard treatment. Conclusions Standard IFX induction regimen is ineffective in achieving relevant post-induction trough levels (&amp;gt;5 mg/L) in the majority of PIBD patients regardless of IFX type. We suggest that optimization of initial IFX prescribing based on baseline albumin (i.e. a higher dose given to patients with albumin &amp;lt; 30g/L) and subsequent levels will improve post-induction trough levels and consequently clinical outcomes for a greater proportion of patients. Funding Agencies None

Body Composition Using Air Displacement Plethysmography in Children With Inflammatory Bowel Disease.

The aim of the study was to assess the body composition of children with inflammatory bowel disease (IBD) and to study the accuracy of clinically available tools in predicting excess body fatness. We aimed at also exploring the influence of adiposity on pharmacokinetics during early Infliximab exposure. Prospective cohort study in 5- to 17-year-old children with IBD initiating Infliximab therapy. Patient demographic, phenotypic, and laboratory data at the time of Infliximab initiation were recorded. Body composition was assessed using air displacement plethysmography (ADP). fat mass index (FMI = fat mass [kg]/(height [m])) was calculated to determine excess adiposity (defined as FMI ≥75th centile). Anthropometrics (weight, height, mid upper arm circumference [MUAC] and triceps skin fold thickness [TSF]) were obtained and MUAC and TSF measurements were used to calculate arm fat area (AFA) and arm muscle area z-scores. Statistical analysis was applied as appropriate. Fifty-three (68% male; 55% Crohn disease [CD], 45% ulcerative colitis [UC], median [IQR] age 15 [13-16] years) children with IBD were included. Twenty-four percentage of children with IBD (21% CD, 29% UC) had excess adiposity. Four children (31%) with FMI ≥75th centile were not identified by body mass index (BMI) alone (kappa of 0.60), and 2 children (15%) were not identified by AFA z-score alone. The intra- and interobserver reliability of MUAC and TSFT measurements was excellent. There was no difference in Infliximab trough levels at the end of induction between those with FMI less than or ≥75th centile. Excess adiposity affects approximately 1 in 4 young patients with IBD and can be missed by routine obesity screening. Our exploratory study did not raise concerns of underexposure to infliximab in those children with excess adiposity during early drug exposure.

OP38 Top-down infliximab superior to step-up in children with Moderate-to-Severe Crohn’s disease: A multicentre randomised controlled trial

Abstract Background In newly diagnosed paediatric Crohn’s disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but mostly used once patients are refractory, the so-called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective if initiated earlier in the disease course. We investigated whether initiation of IFX directly after diagnosis of moderate-to-severe CD, i.e. top-down (TD) treatment, results in a higher long-term remission rate compared with SU treatment. Methods For this international randomised controlled trial (RCT) patients aged 3–17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) &amp;gt;40 were included. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone combined with AZA as a maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. The primary endpoint of this study was sustained clinical remission (wPCDAI &amp;lt;12.5) at week 52 without the need for additional therapy or surgery. Secondary endpoints included patient rate using IFX at week 52, mucosal healing (SES-CD &amp;lt;3) and low faecal calprotectin levels (&amp;lt;250 μg/g) at week 10. Results 100 patients were included in 12 centres. Three out of 100 patients did not start with the study after randomisation (n = 97; 49 TD vs. 48 SU). At 52 weeks, 21/48 (44%) of TD patients were in clinical remission without a need for treatment intensification or surgery, while in the SU group this number was significantly lower (8/48, p = 0.004). After induction therapy, IFX was (re)started in 19/49 (39%) TD patients compared with 30/48 (62%) SU patients within 52 weeks (p = 0.019). At week 10, significantly more TD (27/44, 61%) than SU treated patients (17/44, 39%) were in clinical remission (p = 0.033). Fifty-seven of 97 consented to endoscopy at week 10. Endoscopic remission rates were higher in TD (16/27 [59%], median SES-CD 1 [IQR 0–5]) than SU treated patients (5/30 [17%], median SES-CD 6 [IQR 3–16], p = 0.001). Similarly, low faecal calprotectin levels were more frequent in the TD group (n = 75; TD 21/40 [53%] vs. SU 9/35 [26%], p = 0.027). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. TD treatment was superior to SU in achieving sustained clinical remission. Therefore, we advise to start IFX directly after diagnosis in moderate-to-severe paediatric Crohn’s disease patients.

P797 The inexorable increase of biological exposure in paediatric inflammatory bowel disease: a Scottish population-based, longitudinal study 2015–2019

Abstract Background The use of biologics in paediatric inflammatory bowel disease (PIBD) is rapidly changing with the introduction of new mode of action medications, cheaper biosimilar alternatives, improved convenience with home care options and an increasing focus on early intensified management. No nationwide paediatric data is available to objectively capture this shifting landscape and its effect on healthcare resources. We aimed to identify the incidence and prevalence of biologic use within Scottish PIBD services. Methods In Scotland, specialist paediatric gastroenterology, hepatology and nutrition (PGHAN) services are coordinated through three tertiary academic centres (Glasgow, Edinburgh and Aberdeen) which act as regional referral hubs covering all district general hospitals. A nationwide cohort of prospectively identified PIBD cases less than 18 years of age with paediatric-onset IBD (A1 phenotype; diagnosed &amp;lt;17 years of age) were captured within paediatric services over a 4.5-year period (01.01.2015–30.06.2019). All patients who received infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) or ustekinumab (UST) during the study period (prevalent cases) or received their first dose of these biologics (incident cases not including biosimilar switches) were retrospectively audited. Point prevalence was calculated on 30 June each year and period prevalence as 6 month epochs. Results In total 495 incident new start biological therapies were commenced on 403 PIBD patients over the study period; 295 IFX (60%), 161 ADA (32%), 24 VDZ (5%), 15 UST (3%). The proportion of new start biologics changed over time with IFX initiation rates decreasing (87–54%) while ADA (13–31%), VDZ (0–10%) and UST (0–6%) all increased. Biosimilar penetration of new start anti-tumour necrosis factor (anti-TNF) biologics increased from 3% to 91% by 30.06.2019. The overall number of prevalent PIBD patients increased from 554 to 644 over the study period. Point prevalent rates of current biologic therapy usage increased from 20.2% on 30.06.15 to 43.5% on 30.06.19; an average annual percentage increase of 29%. Conclusion Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing PIBD treatment landscape with a significant increase in biologic therapy (from 20% to 43% in just 4 years), a near-complete shift to biosimilar anti-TNF and use of biologics with new modes of action which are as yet unlicensed for PIBD.

High body mass index is not associated with increased treatment failure in infliximab treated pediatric patients with inflammatory bowel disease.

Background and AimWhile weight gain during infliximab therapy in inflammatory bowel disease (IBD) is common, there has been limited research evaluating its impact on infliximab efficacy.MethodsPrimary aims of this study were to determine the frequency of excess weight gain (body mass index [BMI] > 25 kg/m2) in children with IBD on maintenance infliximab and evaluate the impact on infliximab dosing, serum trough levels, and treatment failure. Secondary aims were to determine differences in weight gain, treatment characteristics, and clinical/biochemical variables between patients with therapeutic and subtherapeutic maintenance therapy trough levels. We performed a retrospective study of 253 pediatric IBD (75.1% Crohn's disease, 23.3% ulcerative colitis, 1.6% IBD‐unclassified) patients on infliximab followed at BC Children's Hospital between January 2013 and January 2018.ResultsMedian age at infliximab initiation was 13.9 years, median length of follow up was 56.9 months, and 55.7% were males; 10.3% of the cohort demonstrated excess weight gain (7.5% overweight, 2.8% obese). Average mg/kg dosing was not statistically different between groups (normal, overweight, and obese: 6.7, 6.4, and 6.7 mg/kg, respectively, P = 0.52). Median BMI of patients with therapeutic and subtherapeutic trough levels was similar at 19.9 kg/m2 (interquartile range [IQR], 17.3–23.8) and 19.7 kg/m2 (IQR, 17.4–21.9), respectively. BMI had no effect on secondary loss of response to infliximab, with no significant difference between normal and high BMI subgroups (13.4 vs. 16.7%, P = 0.9).ConclusionsIn a subgroup of pediatric IBD patients on maintenance infliximab, excess weight gain was not associated with higher weight‐based dosing, lower serum trough levels, or increased risk of treatment failure.

High-dose, high-frequency infliximab: A novel treatment paradigm for hidradenitis suppurativa

The permanent disfigurement associated with hidradenitis suppurativa (HS) necessitates early aggressive disease intervention. Although limited data support the use of infliximab (IFX) in HS, the efficacy of high-dose, high-frequency IFX has yet to be defined. To evaluate the efficacy of IFX 7.5 to 10mg/kg, with a maintenance frequency every 4weeks. Prospective analysis of 42 patients initiating IFX 7.5mg/kg every 4weeks (IFX 7.5) and 16 patients receiving dose escalation to IFX 10mg/kg every 4weeks (IFX 10) between March 1, 2018, and February 28, 2019. The primary outcome measure (clinical response) was the proportion of patients with Physician Global Assessment of clear, minimal, or mild (score of 0-2) HS with at least a 2-grade improvement from baseline scores. The proportion of patients achieving a clinical response after initiating IFX 7.5 was 20 of 42 (47.6%) at week 4 and 17 of 24 (70.8%) at week 12. For patients receiving dose escalation to IFX 10 because of incomplete initial response, 6 of 16 (37.5%) achieved clinical response at week 4 and 6 of 12 (50%) at week 12. Initiation of IFX 7.5 every 4weeks, with possible dose escalation to IFX 10, if needed, provides optimal mitigation of HS-related disease activity.

Infliximab for Refractory Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is frequently difficult to treat. Infliximab (IFX) is useful for extracardiac sarcoidosis, but its use in CS has been limited due to concerns about cardiotoxicity and an FDA blackbox warning about use in heart failure. We reviewed 36 consecutive patients treated with infliximab for CS refractory to standard therapies. IFX was initiated for patients with refractory dysrhythmias, moderate to severe cardiomyopathy, and evidence of persistent F-18 fluorodeoxyglucose uptake on positron emission tomography scan, despite standard therapies. We compared the prednisone dose, ejection fraction (EF), and dysrhythmias before and after IFX therapy. The prednisone-equivalent steroid dose decreased from a median of 20 mg at initiation of infliximab to 7.5 at 6 months and 5 mg at 12 months postinitiation of infliximab (p <0.001). In the 25 patients with serial EF measurements, no statistically significant difference was detected in EF (41% at baseline, 42% at 6 months). Of the 16 patients with serial dysrhythmia data, there was a trend toward reduction of percent of patients with ventricular tachycardia (VT), from 32% at baseline, to 22% at 6 months and 19% at 12 months (p = 0.07). Adverse events were common, occurring in 6 of 36 patients, with 3 of 36 patients stopping infliximab for a prolonged period. In responder analysis, 24 patients improved in at least 1 of 3 outcome categories. In conclusion, infliximab may be useful for refractory cardiac sarcoidosis.

Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease.

In adult inflammatory bowel disease (IBD) treated by anti-TNF antibodies, paradoxical psoriasis has an estimated prevalence of 1.6 to 22%, especially in infliximab (IFX)-treated patients. Little is known in the pediatric IBD (PIBD) populations. All patients ages from 2 to 18 years with Crohn disease (CD) or ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014, were considered for inclusion in this retrospective study performed in a tertiary PIBD centre. Paradoxical psoriasis events together with clinical and biological data were collected in all patients. Comparisons between psoriasis and control groups were performed using univariate statistical analyses. One hundred and twenty-three CD patients and 24 UC patients were treated with IFX. Twenty patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (P = 0.033). Fourteen patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, interquartile range [IQR] 239; 532) after the initiation of IFX corresponding to the eighth injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy. 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). Crohn disease patients with perianal disease were at a higher risk to develop this common side effect.

Quantification of pulmonary disease activity in sarcoidosis measured with 18F-FDG PET/CT: SUVmax versus total lung glycolysis

Background18F-FDG PET/CT has proven to be a reliable tool for therapy monitoring in sarcoidosis. Previous PET studies investigated the SUVmax as a marker for disease activity. Total lung glycolysis (TLuG) is a new tool, quantifying the glycolysis of the entire lung. Since SUVmax represents the maximum activity in only one pixel, we hypothesize that TLuG is a more accurate marker for active pulmonary disease and predictor of response than SUVmax.MethodsIn this retrospective cohort study, 27 patients started on infliximab for refractory pulmonary sarcoidosis. Patients received infliximab intravenously monthly at a dose of 5 mg/kg. We performed a lung function test and an 18F-FDG PET/CT before initiation of infliximab and after 6 months of treatment. SUVmax and TLuG were determined in the pre- and post-scan. Change in lung function was correlated with the change in SUVmax and TLuG and was correlated to the initial SUVmax and TLuG to evaluate the predictive value of the initial metabolic activity.ResultsΔSUVmax significantly correlated with ΔFVC (r = − 0.497, p = 0.008) and with ΔFEV1 (r = − 0.467, p = 0.014). Furthermore, ΔTLuG significantly correlated with ΔFVC (r = − 0.430, p = 0.025), ΔFEV1 (r = − 0.532, p = 0.004) and ΔDLCOc (r = − 0.423, p = 0.039). Change in SUVmax and TLuG significantly correlated (r = 0.735, p < 0.001). Initial SUVmax significantly correlated with the change in FVC and DLCOc. In addition, initial TLuG significantly correlated with the change in FEV1 and DLCOc.A SUVmax > 7.5 at initiation of infliximab was predictive for 5% response in FVC, whereas SUVmax > 9.2 was predictive for 5% response in DLCOc. In addition, high TLuG > 4100 at initiation of infliximab was predictive for 5% response in FVC and FEV1 and TLuG > 4500 was predictive for response in DLCOc.ConclusionSUVmax and TLuG are equal in determining the response to infliximab in pulmonary sarcoidosis patients. Furthermore, SUVmax and TLuG at initiation of infliximab can predict change in lung function after treatment. Since TLuG is a more time-consuming tool, we recommend to use SUVmax of the lung parenchyma for response monitoring in pulmonary sarcoidosis.

Healthcare resource utilization and treatment costs of Finnish chronic inflammatory bowel disease patients treated with infliximab

Objectives: Inflammatory bowel disease (IBD) is associated with a high economic burden to society due to its early onset and chronic character. Here, we set out to characterize healthcare resource utilization and associated costs in Crohn’s disease (CD) and ulcerative colitis (UC) patients with infliximab treatment, the most widely used first-line biologic agent in Finland, in a real-world clinical setting.Methods: This was a retrospective, non-interventional single-center study. Infliximab was administered in routine care, and data were collected retrospectively from electronic health records. All adult anti-TNF naïve CD or UC patients whose infliximab treatment was initiated at the Hospital District of Southwest Finland between the years of 2014 and 2016 were included in the study. Each patient was followed-up for 12 months after the initiation of infliximab treatment.Results: A total of 155 patients were included (45 CD, 110 UC). Altogether, 60.0% (n = 27) of all CD patients and 43.6% (n = 48) of all UC patients persisted on infliximab therapy 12 months after treatment initiation. The total cost was similar for both CD and UC cohorts (CD, €10,243; UC, €10,770), infliximab treatment being the highest individual cost (60.3% of the total cost in CD; 53.4% in UC). The mean number of infliximab infusions during the 12-month follow-up was 7.0 for CD and 6.5 for UC patients.Conclusions: IBD causes a significant burden to the Finnish healthcare system. This study provides a detailed characterization of the cost landscape of IBD and contributes to optimizing treatment strategies and healthcare resource use in the biosimilar era.

Successful treatment with infliximab after adalimumab failure in pediatric noninfectious uveitis

To describe the use of infliximab after adalimumab failure in the treatment of pediatric noninfectious uveitis. A retrospective analysis was performed on the medical records of pediatric patients with noninfectious uveitis treated with infliximab for a minimum of 6months after previously failing to achieve steroid-free remission using adalimumab at the University of Texas Medical School and Children's Medical Center between September 2015 and March 2018. Rates of achieving disease activity quiescence and steroid-free remission as well as incidence of adverse events were calculated. A total of 13 patients with noninfectious uveitis refractory to treatment with adalimumab met inclusion criteria. Three (23%) had anterior uveitis, 4 (31%) had pars planitis, and 6 (46%) had panuveitis. Eleven (85%) patients had preexisting ocular comorbidities. Of these, 4 (31%) had retinal vasculitis, and 1 (7.7%) had cystoid macular edema. There was a 100% response rate to treatment with infliximab following failure to achieve disease quiescence on adalimumab. At mean follow-up time of 21months (range, 8-31) from initiation of infliximab, there was a reduction in steroid dependence from 100% to 15% after transitioning from adalimumab to infliximab (P<0.001). Nine patients (69%) had achieved steroid-free remission on infliximab therapy. The mean time to steroid-free remission was 8.7months. In our study cohort, infliximab was used successfully in all cases of recalcitrant pediatric noninfectious uveitis that previously failed adalimumab therapy.

Predictors of relapse following infliximab de-escalation in patients with inflammatory bowel disease: the value of a strategy based on therapeutic drug monitoring.

There are limited data concerning infliximab drug monitoring during de-escalation of the treatment of inflammatory bowel disease (IBD). To define the rate and the predictors of relapse following infliximab de-escalation in IBD patients in remission. All IBD patients at a single referral centre in clinical and biological remission and in whom the dose of infliximab had been de-escalated were included. Patients in remission with a high trough level of infliximab (>7mg/L) were considered to be trough level-based de-escalation patients. The data were retrieved from a prospective IBD database. Actuarial analysis was performed for statistical purposes. A total of 146 de-escalations were performed in 96 patients (Crohn's disease/ulcerative colitis: 68%/32%); 54 (37%) were based on clinical remission only, and 92 (63%) were based on clinical remission associated with a trough level above 7mg/L. The cumulative probabilities of relapse following infliximab de-escalation were 16% and 47% at 1 and 2years, respectively. Ulcerative colitis was associated with an increased risk of relapse (HR=3.2, P=0.005). Conversely, combination therapy at infliximab initiation (HR=0.39, P=0.0110) and trough level-based de-escalation were associated with decreased risk of relapse (HR=0.45, P=0.024). Trough levels before and after de-escalation were well correlated; a decrease by half was observed following a 2-week interval increase or a half-dose decrease. The use of trough levels to assess the feasibility of dose de-escalation seems to be a prerequisite for decreasing the risk of relapse.

Assessment of endothelial function during the loading phase of infliximab in psoriasis: a potential predictor of its drug survival.

Tumor necrosis factor inhibitors decrease the risk of cardiovascular events in moderate to severe psoriasis, but the association between their effects on endothelial function and those on skin lesions has not been well studied. We investigated the association between infliximab effects on endothelial function during the loading phase and those on skin lesions in patients with psoriasis. We evaluated endothelial function with reactive hyperemia-peripheral arterial tonometry index (RHI) in 15 patients with psoriasis before the first and third infusions of infliximab. Patients were stratified into two groups; those who maintained Psoriasis Area and Severity Index (PASI) 75 response for more than 6 months (defined as responders) and the others (defined as nonresponders). Six weeks after the initiation of infliximab (before the third infusion), PASI scores were significantly improved compared with baseline, while RHI values were not altered in the whole patient group. However, when the responders and the nonresponders were analyzed separately, RHI values tended to be decreased before the third infusion compared with baseline in the nonresponders, while being unchanged in the responders. Importantly, the difference in ∆RHI reached a statistical significance between the two groups, and the cutoff value (mean - 2 standard deviation of RHI values in the responders) identified the nonresponders with 67% of sensitivity and 100% of specificity. The decrease in RHI values before the third infusion may serve as a predictor for the long-term unfavorable effect of infliximab on psoriatic skin lesions.

Early Initiation of Tumor Necrosis Factor Antagonist–Based Therapy for Patients With Crohn’s Disease Reduces Costs Compared With Late Initiation

Antagonists of tumor necrosis factor (TNF) are effective for induction and maintenance of remission of Crohn's disease (CD) and are generally prescribed when patients do not respond to conventional, less-costly medical therapies. Early initiation of anti-TNF therapy reduced rates of surgery and dose escalation due to loss of response. However, these drugs are expensive, so studies are needed on the cost effectiveness of early initiation. We aimed to determine the cost effectiveness of initiating treatment early in the disease course (within 2 years of CD diagnosis) vs later in the disease course (more than 2 years after diagnosis). We constructed a Markov model of a hypothetical cohort of patients with CD in Canada to simulate disease progression after initiation of infliximab or adalimumab therapy. We used published loss-of-response rates to compare the lifetime cost effectiveness of early vs late initiation of anti-TNF therapies. Transition probabilities and utilities were obtained through a literature search, and costs were obtained from the Alberta Ministry of Health. Sensitivity analysis was used to characterize uncertainty. Early initiation of infliximab yielded an additional 0.72 quality-adjusted life-years (QALYs) and saved $50,418 compared with late initiation. Early initiation of adalimumab yielded an additional 0.54QALYs and saved $43,969. At a willingness-to-pay threshold of $50,000, early initiations of infliximab or adalimumab therapy had a 74% chance of being cost effective compared with late initiation. In a Markov model analysis, we found initiation of either infliximab or adalimumab within 2 years of CD diagnosis to provide significant cost savings and QALYs compared with later initiation (more than 2 years after diagnosis).

Accelerated Step-Up Infliximab Use Is Associated with Sustained Primary Response in Pediatric Crohn's Disease.

Earlier introduction of infliximab (IFX) in Crohn's disease (CD) may be associated with a sustained remission. Children on scheduled IFX therapy for predominant luminal CD after successful induction (drop in PCDAI by≥15) and a minimum of 2-year IFX follow-up were included. We compared outcomes of children treated with early (within 3months from diagnosis) versus later IFX (after failing conventional therapy≥3months) and identify clinical predictors of sustained primary response (SPR) in our cohort. SPR was defined as CS-free clinical remission without requiring IFX dose escalation and/or surgical excision and/or switch to second anti-TNFs due to LOR or allergic reaction. Sixty-four children received IFX therapy for CD during the study period. Forty-three children on scheduled IFX therapy for luminal CD met the inclusion criteria. During the median follow-up of 3.05years (IQR 2.6-3.5years), SPR was observed in 17/43 (40%). SPR was associated with shorter time from diagnosis to the initiation of IFX (5.4 vs. 18.7months, p=0.006). Binary logistic regression using multiple variables also confirmed that only early use of IFX is associated with SPR. Early step-up use of IFX in children with CD with inadequate clinical response to conventional therapies leads to sustained primary response over 2years.

P569 Outcomes of IBD patients treated with infliximab: The impact of therapeutic drug monitoring in real-life clinical practice

Infliximab (IFX) is a recognised treatment for inflammatory bowel disease (IBD).1 Therapeutic Drug Monitoring (TDM) includes measurement of Infliximab trough levels and antibodies to Infliximab (ATI) to optimise treatment and personalise care.2 We aim to explore the clinical outcomes of TDM for IBD patients on IFX in a real-life setting. This is a retrospective observational study. Patients on IFX were identified by screening our biologics audit database. TDMs were tested using standard protocol. Primary outcome measure was the rate of IFX discontinuation. Secondary outcomes include the rate of intestinal surgery after IFX initiation and remission rate 6-months after every TDM test. Multivariate binary logistic regression [OR, (95% CI), p value) was performed to identify factors associated with IFX discontinuation and abdominal surgery. Three hundred and forty patients were included with a mean (SD) follow-up of 49.1 (32.7) months. Two hundred and ninety-one had Crohn’s disease (CD) and 49 ulcerative colitis (UC) with mean (SD) age of 38.0 (13.5) and 41.6 (15.7) years, respectively. Two hundred and seventy-nine (82.1%) patients (238 CD and 41 UC) were tested for TDM at least once during their follow-up with 759 TDM results. Five hundred and eighty-four (76.9%) TDMs results did not alter patient management. Clinical remission 6 months after TDM testing was associated with 468 (61.7%) TDM tests. One hundred and twelve of 179 patients (40.1%) had undetectable levels and 90 (32.3%) had positive ATI at least once during their follow-up. The mean (SD) Infliximab trough level was 4.1 (3.2) μg/ml. One hundred and sixty-nine patients (49.7%) had their treatment with Infliximab discontinued during the course of follow-up. Treatment was discontinued in 56 (91.8%) patients who were never tested for TDM compared with 113 (40.5%) tested for TDM (p < 0.01). Fewer TDM tested patients (32; 11.5%) required intestinal surgery post IFX initiation compared with TDM not-tested group (17; 27.9%) (p < 0.01). TDM was independently associated with IFX discontinuation [OR 19.1, (7.1, 51.2), <0.01] and need for intestinal surgery after IFX initiation [2.2, (1.03, 4.6), 0.04]. Treatment failure with IFX discontinuation and surgery was significantly less frequent with TDM. TDM did not alter management in majority of cases; this may be due to repetitive test to look for transient ATI or to assess effect of treatment adjustment or equivocal indication of annual testing. Further analysis will study outcomes for specific TDM indications. 1. Hanauer SB et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet, 2002;1541–1549. 2. Niels Vande Casteele et al. Trough concentrations of Infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology, 2015;1320–1329.