Infliximab Infusion Research Articles

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

Transitioning patients with inflammatory bowel disease from hospital-based to rapid home-based infliximab: A stepwise, safety and patient-orientated process towards sustainability.

BACKGROUNDInfliximab and other intravenous biologic infusions are increasingly used for chronic disorders like inflammatory bowel disease (IBD). Rapid infliximab and home-based infusions are attractive solutions to address resource and capacity issues for infusion centres, yet infliximab infusion reactions reportedly occur in up to 25% of patients with IBD, even at the manufacturers’ recommended infusion duration of 2 h.AIMTo evaluate the safety, cost and patient satisfaction of transitioning from hospital-based, standard 2 h to rapid home-based, 30-min infliximab infusions.METHODSAll patients receiving rapid infliximab infusions for IBD between 2014 to 2017 (39 mo) were compared with those who received standard two-hour IFX infusions between 2005-2013 (96 mo) at a single IBD centre. Data (per-infusion and per-individual) including adverse drug reactions (ADR), duration (based on needle-departure time) and other clinical data were extracted from electronic medical records. Multivariable logistical regression analysis assessed factors potentially associated with increased risk of ADRs to rapid infusions. The primary outcome was the safety [as per relative risk (RR) of ADR] of (1) rapid 30 m infusions (both hospital- and home-based) vs standard 2 h infliximab infusions. Also, relative cost per infusion and patient satisfaction and productivity were evaluated in rapid infusion recipients who transitioned to home-based infusions.RESULTSOf 129 patients who received 1461 rapid IFX infusions (2014-2017) were compared with 169 patients who received 2214 standard IFX infusions (2005-2013). Within the rapid cohort, 55 (42.6%) were males, median age 42 years (range 18, 86), 114 (84%) had Crohn’s disease (CD) with a median disease duration 5 years (0, 36). Median needle to departure time was higher in the standard than the rapid protocol group, 108 (70, 253) vs 50 (33, 90) min, P < 0.001), with a per infusion cost of $AUD 107.50 vs $49.77, respectively (both P < 0.001). There was no difference in median infusion duration or costs between rapid home vs hospital-based infusions (P = 0.21). 8 patients in the rapid infliximab cohort had an ADR compared with 23 standard infliximab recipients (RR 0.55% vs 1.04% respectively), hence a higher likelihood of ADR with standard compared to rapid infusions [RR 3.0, 95%CI (1.2, 7.7), P = 0.02]. No ADRs were observed in 405 rapid home-based infusions. A lower body mass index (< 22 kg/m2), presence of one or more extra intestinal manifestations, longer disease duration (> 3 years) and previous exposure to another biologic were each independently associated with a higher likelihood of reaction (s) to rapid infusions. All (100%) survey respondents preferred the rapid vs standard infusions, however within rapid infusion recipients, 61.3% found home based infusions more inconvenient than hospital-based infusions despite a median of 0 h per week missed from paid work and no self-reported loss of work productivity.CONCLUSIONTransitioning to rapid infliximab infusions appears very safe with significant cost benefit, patient satisfaction and avails the provision of safe, efficient, home-based infliximab infusions by IBD centres worldwide.

The Efficacy of Antihistamines in Preventing Reactions to Infliximab in Patients With Crohn Disease/Ulcerative Colitis: A Review of the Evidence.

Inflammatory bowel diseases, including Crohn disease and ulcerative colitis, are most often diagnosed during adolescence and young adulthood, with a rising incidence in pediatric populations. Infliximab is an effective treatment option for Crohn disease and ulcerative colitis. The most common adverse event with infliximab is an infusion reaction. Patients are often treated prophylactically with combinations of acetaminophen, intravenous steroid, and an antihistamine to prevent an infusion reaction. There is a high degree of practice variation regarding pretreatment for infliximab infusions, the efficacy of pretreatment with an antihistamine is unproven in preventing infusion-related reactions, and there is no national clinical standard. Unnecessary pretreatment in adolescence and young adulthood may be harmful, as this is a time to focus on developing self-care management skills. Antihistamine side effects including somnolence and dizziness may adversely affect adolescents and/or young adults' ability to complete schoolwork, drive, and transition toward autonomous management of their chronic illness. This report presents the findings of an evidence-based practice project reviewing the efficacy of pretreatment with an antihistamine in patients with Crohn disease and ulcerative colitis receiving infliximab. Practice implications are discussed.

Infliximab Level Between Venous and Capillary Blood Using Novel Device Strongly Correlate in Paediatric Inflammatory Bowel Disease Patients.

Blood to measure infliximab (IFX) levels is typically obtained with venipuncture. Dried blood sampling (DBS), using capillary blood obtained from a finger prick, would be an alternative to measure IFX blood levels while being more patient friendly. The aim of this study is to compare IFX blood level measured by venipuncture versus DBS in patients with paediatric inflammatory bowel disease (PIBD) to assure accuracy. A prospective clinical pilot study was performed in patients with PIBD. Before IFX infusion, blood was collected simultaneously through venipuncture and DBS from a finger prick, using Mitratips (Neoteryx). All IFX concentrations were measured by an enzyme-linked immunosorbent assay. The Bland-Altman analysis was used to measure limits of agreement. The interrater reliability was measured with the interclass correlation coefficient and Cohen kappa. To calculate Cohen kappa, IFX levels were categorized into 3 groups; low <5 μg/mL, adequate 5 to 10 μg/mL, and high >10 μg/mL. Twenty patients were included. Median age was 12.1 year (interquartile range 8-16 year). The mean difference between the 2 methods was -0.14 as calculated with Bland-Altman plot. The limits of agreement were between -1.39 and 1.12. The interclass correlation coefficient was with 0.998 excellent. The Cohen kappa between 3 IFX level categories was strong K = 0.911 (P = 0.0001). There was a strong correlation between venous IFX serum levels and DBS (r = 0.991, P = 0.0001) in the included patients. This is the first study in patients with PIBD to show that bloodspot technology is a patient friendly alternative method to measure IFX blood levels in PIBD.

Pre-operative withholding of infliximab and the risk of infections after major surgery in patients with rheumatoid arthritis.

Withholding TNF inhibitors (TNFI) before surgery has been recommended due to concern for post-operative infection. We examined the risks of post-operative infections and mortality in patients with RA in relation to the pre-operative timing of infliximab infusion. In this population-based retrospective cohort study, we used US Medicare claims data from 2007 to 2015 to identify patients with RA who underwent coronary artery bypass grafting (CABG), aortic or vascular surgery, or bowel resection, and who were treated with infliximab in the 90 days prior to surgery. We examined associations between the timing of infusion and infections and mortality in the 30 days after surgery. We adjusted for the predicted probability of post-operative infection or death, demographic characteristics, use of MTX, post-operative blood transfusion and hospital volume. We studied 712 patients with CABG, 244 patients with vascular surgery and 862 patients with bowel resections. Post-operative pneumonia occurred in 7.4-11.9%, urinary tract infection in 9.0-15.2%, surgical site infection in 3.2-18.9%, sepsis in 4.2-9.6% and death in 3.5-7.0% among surgery cohorts. There was no association between the time from last infliximab dose to surgery and the risk of post-operative infection or mortality in any surgical cohort. No subgroups were identified that had an increased risk of infection with more proximate use of infliximab. Among elderly patients with RA, risks of infection and mortality after major surgery were not related to the pre-operative timing of infliximab infusion.

Home Infliximab Infusions Are Associated With Suboptimal Outcomes Without Cost Savings in Inflammatory Bowel Diseases.

Biologic agents including infliximab are effective but costly therapies in the management of inflammatory bowel disease (IBD). Home infliximab infusions are increasingly payer-mandated to minimize infusion-related costs. This study aimed to compare biologic medication use, health outcomes, and overall cost of care for adult and pediatric patients with IBD receiving home vs office- vs hospital-based infliximab infusions. Longitudinal patient data were obtained from the Optum Clinformatics Data Mart. The analysis considered all patients with IBD who received infliximab from 2003 to 2016. Primary outcomes included nonadherence (≥2 infliximab infusions over 10 weeks apart in 1 year) and discontinuation of infliximab. Secondary outcomes included outpatient corticosteroid use, follow-up visits, emergency room visits, hospitalizations, surgeries, and cost outcomes (out-of-pocket costs and annual overall cost of care). There were 27,396 patients with IBD (1,839 pediatric patients). Overall, 5.7% of patients used home infliximab infusions. These patients were more likely to be nonadherent compared with both office-based (22.2% vs 19.8%; P = .044) and hospital-based infusions (22.2% vs 21.2%; P < .001). They were also more likely to discontinue infliximab compared with office-based (44.7% vs 33.7%; P < .001) or hospital-based (44.7% vs 33.4%; P < .001) infusions. On Kaplan-Meier analysis, the probabilities of remaining on infliximab by day 200 of therapy were 64.4%, 74.2%, and 79.3% for home-, hospital-, and office-based infusions, respectively (P < .001). Home infliximab patients had the highest corticosteroid use (cumulative corticosteroid days after IBD diagnosis: home based, 238.2; office based, 189.7; and hospital based, 208.5; P < .001) and the fewest follow-up visits. Home infusions did not decrease overall annual care costs compared with office infusions ($49,149 vs $43,466, P < .001). In this analysis, home infliximab infusions for patients with IBD were associated with suboptimal outcomes including higher rates of nonadherence and discontinuation of infliximab. Home infusions did not result in significant cost savings compared with office infusions.

Safety of Rapid Infliximab Infusions in Children: A Systematic Review.

The aim of the study was to assess whether the incidence of infusion reactions (IR) increases after rapid (≤1 hour) infliximab (IFX) infusions, compared with standard (2-3 hour) infusions in children. Systematic review including studies describing the number of IR after rapid IFX infusion in children ages 0 to 18 years. Four records were included (3 retrospective, n = 498, 347 standard infusions, 3703 rapid infusions). Reported incidences of IR ranged from 0% to 2% of infusions in standard groups (reported 95% confidence intervals [CIs] ranged from 0% to 7%) and from 0% to 2% of infusions in rapid groups (reported 95% CIs ranged from 0% to 12%). None of the studies included reported a significant difference in incidence of IR between the 2 groups. There is insufficient evidence to conclude whether the rate of IR after rapid IFX increases. The consistent finding of no increase in IR in all studies and the low rate of observed IR suggests there is no significant difference in rate of IR.

Effectiveness of Infliximab on Deep Radiological Remission in Chinese Patients with Perianal Fistulizing Crohn's Disease.

Information concerning deep radiological healing of perianal fistulas in Chinese patients with CD is limited. The present study aimed to establish the effectiveness of infliximab on CD-related perianal fistulas using magnetic resonance imaging (MRI) and identify predictors of deep radiological remission of fistulas. We retrospectively reviewed patients with CD with draining perianal fistulas treated with infliximab and included only those who underwent clinical assessment and MRI before and after infliximab therapy. Among 178 patients who underwent repeated MRI and clinical assessment, 65.2% had complex fistulas. Post-infliximab therapy, 55.1% of patients with perianal fistulizing CD showed clinical remission and 26.4% presented a clinical response; 38.2% had deep radiological remission, and 34.3% had a partial response based on the Ng score; the Van Assche scores decreased obviously compared with baseline. Prolonged infliximab infusion (18 times) presented higher radiological remission rates in patients with CD with complex fistulas. Concomitant treatment with azathioprine increased the fistula healing rate compared with infliximab alone (50% vs. 36.9%, P < 0.001). Younger age at diagnosis of CD, proctitis and requiring perianal surgery were identified as predictors of poor deep radiological remission of fistulas. Eight of ten patients who stopped infliximab and switched to an alternative agent retained a status of fistula healing in the first year of follow-up. Infliximab induced deep radiological remission of perianal fistulas in Chinese patients with CD. Routine MRI should be used to monitor fistula healing. Patients with younger age at diagnosis of CD, proctitis, and/or requiring perianal surgery should receive combined therapy and careful monitoring.

Changes in the Intestinal Microbiota of Patients with Inflammatory Bowel Disease with Clinical Remission during an 8-Week Infliximab Infusion Cycle

This study investigated changes in the intestinal microbiota during 8-week infliximab maintenance therapy in inflammatory bowel disease (IBD) patients in clinical remission. Microbial compositional differences were analyzed according to the trough level of infliximab (TLI) and mucosal healing (MH) status. 16S rRNA gene-based microbiome profiling was performed on 10 and 74 fecal samples from 10 healthy volunteers and 40 adult IBD patients, respectively. Fecal sampling occurred at 1–2 weeks (1W) and 7–8 weeks (7W) after infliximab infusion. TLI was measured by ELISA at 8 weeks, immediately before the subsequent infusion; MH was evaluated by endoscopy within 3 months. There were no significant changes in microbial composition, species richness, or diversity indices between 1W and 7W. However, 7W samples from the patients with TLI ≥ 5 μg/mL showed an increased species richness compared with patients with TLI < 5 μg/mL, and patients with MH showed increased diversity compared with non-MH patients. Beta-diversity analysis showed clustering between samples in the MH and non-MH groups. LEfSe analysis identified differential composition of Faecalibacterium prausnitzii group according to TLI and MH. In conclusion, these results suggest the potential of fecal microbiota as a response indicator.

Biosimilar Uptake in Academic and Veterans Health Administration Settings: Influence of Institutional Incentives.

To compare uptake in the ordering of biosimilars at a Veterans Affairs Medical Center (VAMC) to that at an academic medical center, where institutional incentives for infused medications differ. We performed a cross-sectional study of medical record data and estimated institutional financial incentives at 2 medical centers in Philadelphia: 1) the University of Pennsylvania Health System (UPHS), and 2) the local VAMC.All ordering events for filgrastim or infliximab products were quantified over time and stratified according to product (biosimilar versus reference product) and center. Financial incentives to the institutions over time were determined based on actual drug costs for the VAMC and average sales prices (ASPs) and Medicare Part B reimbursement rates for UPHS. There were 15,761 infusions of infliximab at UPHS, of which 99% were for the reference product. There was a sharper decline in the use of reference products at the VAMC; 62% of the 446 infliximab infusions ordered at the VAMC were for the reference product. ASPs were consistently lower for biosimilar infliximab products, but the estimated institutional financial incentives remained similar over time for biosimilar and reference infliximab at UPHS. At the VAMC, the costs for 100-mg vials of reference infliximab and infliximab-abda were $623.48 and $115.58, respectively: a $507.90 (81%) savings per vial. The uptake of infliximab biosimilars has been slow at an academic medical center compared to a nearby VAMC, where financial savings are realized by the institution from its use. Slow adoption of biosimilar medications may impact the rates of decline in costs.

Mucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis

BackgroundImmune-related colitis is a common, often serious complication of immune checkpoint inhibition (ICI). Although endoscopy is not strictly recommended for any grade of diarrhea/colitis, emerging evidence suggests that endoscopic evaluation...

Post-induction infliximab trough levels and disease activity in the clinical evolution of pediatric ulcerative colitis.

Recent adult evidence suggests that infliximab (IFX) trough levels (TL) in patients with severe ulcerative colitis (UC) may be decreased. The aims of our study were to compare post-induction IFX TL of children with severe versus moderate UC and to evaluate short- and long-term outcomes. In this single-center retrospective study, children with a diagnosis of UC starting IFX with a Pediatric Ulcerative Colitis Activity Index (PUCAI) ≥35 and with available post-induction TL were recruited. UC characteristics, IFX dosage and interval, primary non-response, IFX failure, and surgery after 24 months were collected. Post induction TL, anti-IFX antibodies, and laboratory evaluations at the time of starting IFX were also acquired. A total of 90 children were enrolled, of whom 39 (43.3%) were classified as severe UC and 51 (56.6%) as moderate UC. Median post-induction IFX TL were lower in severe UC versus moderate group (5.5 vs 10.3; p = 0.03), despite a more frequently intensified IFX regimen. Children in the higher TL quartiles showed increased rates of clinical, biological, and combined remission (p = 0.04, p < 0.001, and p = 0.01, respectively). In a multivariate analysis, a PUCAI ≥65 and time interval from last IFX infusion were the only predictors associated with IFX TL. At 24 months, children in the higher TL quartiles had a decreased risk of IFX failure (p = 0.002). The severe UC group showed a higher risk of IFX failure at 24 months (16/23 (41%) vs. 11/40 (21.6%); p = 0.05). Kaplan-Meier methods demonstrated a trend toward statistical significance, with a two-year cumulative colectomy rate of 15.38% (95% confidence interval (CI) 8.1-15.6%) in children with severe UC and 3.92% (95% CI 2.9-10.8%) in patients with moderate UC (logrank test p = 0.06). Children starting IFX with severe UC showed lower post-induction TL and poor disease outcomes. Achieving adequate TL was associated with better efficacy outcomes.

Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab

A substantial proportion patients with inflammatory bowel disease (IBD) have a primary non-response to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response. We performed a prospective study of 41 adults with IBD (mean age, 38 years; 21 male; 21 with Crohn's disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) at baseline (before the first infusion) and after 6 weeks (3rd infliximab infusion). PMBCs were obtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. We measured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 or more or decrease in partial Mayo scores of 3 or more at week 6) in patients with PBMCs that produced high vs low levels of TNF. Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn's disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8-148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation. Production of a high level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn's disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.

Uses of infliximab infusion in treatment of ankylosing spondylitis in Iraqi patients

Ankylosing spondylitis refers to the inflammatory disorder associated with fibrous or bony bridging of joints in the spine, including the bridging of intervertebral discs. Objective: To assess the Infliximab Infusion and its Relation on Disease Activity, Severity and Acute Phase Reactant Protein in Iraqi Patients with Ankylosing Spondylitis. Patients and method: Sixty (90) patients were included in this study, were diagnosed as established AS patients who were attending the rheumatology outpatient clinic of Baghdad teaching hospital, thirty (45) patients of them were on conventional treatment (steroid and/or cytotoxic drugs), while the other thirty (45) patients were on biological treatment (infliximab infusion). Mean serum level of matrix metalloproteinase-3 was statistically higher in patient group (4.42 ± 3.05 ng/ml) than control group (2.69 ± 2.57 ng/ml), and also was statistically higher in patients on conventional treatment (5.31 ± 3.16 ng/ml) than those on biological treatment (3.54 ± 2.70 ng/ml). The study shown that matrix metalloproteinase-3 was higher in patient group than control group and also was higher in patients on conventional treatment than in patients on biological treatment.

Corona Virus Disease 2019 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology, and Nutrition.

ABSTRACTIntroduction:With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19.Methods:An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members.Results:Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%.Conclusions:Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other.Supplemental digital content:An infographic accompanying this article can be found at.

A233 VEDOLIZUMAB FOR STEROID & INFLIXIMAB-REFRACTORY ICI-COLITIS

Abstract Background Immune checkpoint inhibitors (ICI), such as anti-PD1, improve survival in melanoma, renal carcinoma and prostate cancer. However, by disinhibiting the immune system, these treatments cause significant immune-related adverse events (irAE), including colitis. For ICI-colitis, guidelines suggest escalating from observation to steroids to infliximab, without strong evidence for additional options should these fail. Vedolizumab has been used in a small number of cases for steroid-refractory or dependent ICI-colitis; only 9 cases have been reported in patients who failed infliximab therapy with a response rate of 67%. Aims To discuss a case of ICI-colitis that failed multiple steroid courses and infliximab infusions, but achieved remission with vedolizumab. Methods A 65-year-old male with malignant melanoma was randomized to adjuvant nivolumab +/- ipilimumab and developed non-bloody diarrhea. Despite loperamide, diarrhea worsened to 4–5 bowel movements daily. Stool cultures and C. diff were negative and 85mg of daily prednisone was started, while the ICI was held for 8 weeks. After a 2nd steroid taper, diarrhea recurred and the patient received 2 infliximab infusions 18 days apart. Despite initial improvement, biopsies demonstrated colitis and he underwent a 3rd infusion with little response. Clinical and biopsy-confirmed remission was only achieved once 2 vedolizumab infusions were given. Results Colitis is the most common ICI irAE, ranging in severity from mild to perforation and death. The incidence of grade 3 and 4 colitis, which require ICI discontinuation, is 1.3% for anti-PD1 and 13.6% in combination therapy. The severity of irAE is positively correlated with malignancy response and stopping ICI risks recurrence. Those that fail irAE medical management may require surgery. Thus, there is an impetus to continue the ICI and provide effective medical management for irAE. ICI-colitis guidelines are based on the CTCAE diarrhea classification and suggest supportive management and ICI continuation for grade 1. For grade 2, the ICI is held and steroids are started; infliximab is added for grades 3 and 4. However, 33–66% of patients are steroid-refractory or dependent; and patients may be infliximab non-responders, or unable to tolerate systemic side effects. Vedolizumab, an anti-α4β7-integrin, acts locally to inhibit T cells in the bowel wall, reducing inflammation in IBD. Recent reports, including ours, suggest usefulness in steroid and infliximab-refractory ICI colitis after only 2–4 infusions. When the inflammatory burden is high, the response rate is &amp;gt;80% and given its gut-specificity, side effects are minimal compared to infliximab. Although further evaluation is required, using vedolizumab as second-line therapy is reasonable. Conclusions Given vedolizumab’s safety and gut-specificity, it should readily be considered in the treatment of ICI irAE. Funding Agencies None

22 CHANGE IN FECAL CALPROTECTIN AND LACTOFERRIN PREDICT CLINICAL REMISSION FOLLOWING INDUCTION THERAPY WITH INFLIXIMAB IN PEDIATRIC CROHN’S DISEASE (CD)

Abstract Background The fecal biomarkers, calprotectin and lactoferrin are noninvasive biomarkers for mucosal inflammation in IBD. While prior cross-sectional studies showed a correlation between these measures, less is known about the relationship of these measurements with treatment response over time. We aimed to assess the correlation between and utility of fecal calprotectin and lactoferrin on treatment response with infliximab (IFX). Methods We analyzed fecal calprotectin (FCP) and lactoferrin (LCT) as part of a multicenter, prospective anti-TNF induction cohort. IFX induction between 5-10mg/kg occurred at 0, 2 and 6 weeks. Stool and serum were collected prior to IFX treatment (baseline) and during follow-up. We evaluated FCP, LCT and trough IFX levels prior to the first and at subsequent infusions up to infusion 4. The primary outcome was the correlations between FCP, LCT, and outcomes at maintenance. Clinical outcomes were assessed by the wPCDAI measured at each infusion. Clinical remission was defined as wPCDAI &amp;lt;12.5. Spearman correlation was used to assess the relationship between FCP and LCT. Predictive outcomes were calculated by receiver operating characteristics (ROC) with Youden-J statistic. Results Among 57 CD patients, 54 (95%) had FCP and LCT measured at both baseline and infusion 4. There was a strong correlation between calprotectin and lactoferrin with data at all time points (R = 0.82, P &amp;lt; 0.0001). The correlation was even stronger at infusion 4 (R = 0.88, P &amp;lt; 0.0001). A delta score for FCP and LCT was calculated by the proportional change between baseline levels to infusion-4 levels. There was a strong correlation between the FCP delta and LCT delta (R = 0.7, P &amp;lt; 0.0001), suggesting similarities in quantifiable change over time. At Infusion 4, an FCP &amp;lt; 378 μg/g predicted sustained clinical remission between week 14 and 6 months with a sensitivity (sens) of 71% and specificity (spec) of 58% (AUC 0.708; P = 0.01). LCT &amp;lt;20.5 μg/g predicted sustained clinical remission between week 14 and 6 months with a sens of 68% and spec of 45% (AUC 0.627; P = 0.117). FCP &amp;lt; 639 μg/g at infusion 4, had a sens of 75% and spec of 75% for achieving an infusion 4 trough level ≥ 5μg/ml (AUC 0.758; P = 0.005). LCT &amp;lt; 34.2 μg/g had a sens of 69% and spec of 54% (AUC 0.692; P = 0.036) for similar trough levels. FCP &amp;lt; 213.6 μg/g at infusion 4, had a sens of 56% and spec of 88% for achieving a infusion 4 trough level &amp;gt; 8μg/ml (AUC 0.744; P = 0.007). LCT &amp;lt; 6.0 μg/g had a sens of 44% and spec of 92% (AUC 0.675; P=0.05) for similar trough levels. Discussion This study demonstrates that both noninvasive biomarkers can be used to predict sustained clinical remission during IFX therapy. It also provides further evidence for the utilization of fecal calprotectin and lactoferrin as predictors to achieve IFX infusion 4 trough level targets for ≥ 5μg/ml and &amp;gt;8μg/ml.

P407 Is the rapid infliximab infusion a safe and cost-saving strategy in paediatric inflammatory bowel disease?

Abstract Background Rapid infliximab (IFX) infusion administered over 60 min is a safe strategy in selected Inflammatory Bowel Disease (IBD) adult patients. Some paediatric studies found similar results among children but data are still scarce. The aim of our study is to evaluate the safety of rapid IFX infusion strategy in our cohort of Paediatric IBD (PIBD) patients and analyze the impact of this strategy on health care resources. Methods Paediatric IBD patients under IFX treatment using standard protocol (2-h IFX infusion), and who had received at least 4 previous standard infusions, with no dose change in the last 2 doses, and without infusion reactions were switched to receive a 1-h IFX infusions. Demographic and clinical data were collected from medical records, and patient and family satisfaction was recorded by a telephone survey. The optimisation of health care resources was also analyzed. Results A total of 46 PIBD patients were under IFX treatment during the study period (February 2018-February 2019) of whom 26 met inclusion criteria and were switched to rapid IFX infusions (14 Crohn’s disease (CD), 12 ulcerative colitis; 17 males). The mean age at switch was 15.3 years (IQR 5.3–17.9) with a mean time of IFX use of 30 months (IQR: 4–78). Sixteen patients were receiving concomitant immunomodulators. A total of 154 rapid IFX infusions were administered with a mean dose of IFX of 5.4 mg/kg (IQR 4–10) and an average frequency of 6.7 weeks (IQR 4–8). No patient received premedication at any time and no infusion reactions were seen during the study period. Family and patient satisfaction (22/26) was higher in rapid IFX infusion strategy than in standard protocol (9.1/10 vs. 7.6/10). During the study period, 154 h of hospitalisation were saved. Conclusion Rapid IFX infusion strategy in selected PIBD patients is safe and well accepted by patients and their families. In addition, it is a cost-saving strategy, minimising the loss of work and teaching hours by the caregivers and patients, and allows optimisation of the hospital resources. These results have led us to establish rapid IFX infusion in selected patients (with stable previous doses and no infusion reactions) as the standard protocol in our centre.

P604 Can we reduce intravenous monoclonal antibody observation times without compromising patient safety? A single centre retrospective observational study

Abstract Background Monoclonal antibodies (MAbs) are integral to inflammatory bowel disease (IBD) management. The administration of intravenous (IV) MAbs, infliximab and vedolizumab, for Brighton and Sussex University Hospital patients is via an outpatient clinic. Licensing specifies lengthy observation times; infliximab for induction (infusion 1 to 3) and maintenance (infusion 4 onwards) requires 1 to 2 h observation. Vedolizumab for induction (infusion 1 to 2) requires 2 h observation and maintenance (infusion 3 onwards) 1-h observation. This can affect waiting times; 33% UK patients waited longer than two weeks for infliximab. A reduction in observation times could improve capacity but needs to be done without compromising patient safety. Methods A single centre observational study was conducted. Retrospective data were collected on all current patients receiving infliximab or vedolizumab at BSUH. Data were collected over 12 weeks (April to July 2019); patients seen twice in this period were included once. The presence of reaction from current and previous infusions was determined by patient questioning and patient records review. Reaction occurrence, nature and management were recorded. There is not a grading system for IBD infusion-related reactions. To standardise we used the cancer Common Terminology Criteria for Adverse Events; grade 3 and above is designated severe (grade 5 being death). Results For infliximab 130 patients were reviewed with 2607 infusions administered in total. For vedolizumab 69 patients were reviewed with 557 infusions administered in total. Due to the small sample size significance could not be reached. The survival plot indicates high levels of ‘no reactions’ observed in the first 4 infusions of infliximab 97.7% (+1.6%, -4.7%), and first 3 infusions of vedolizumab 96.9% (+2.3%, −8.8%). Considering capacity over 12 weeks, for infliximab a minimum of 121 could be recouped and 64 h for vedolizumab. Extrapolated this could equate to 740 h per year. Conclusion All reactions occurred within three infusions, were non-severe and managed within the infusion clinic. By removing the observation period from infusion 4 onwards, infusion clinic capacity could be increased but further data from multiple centres are required to prove significance.

P837 Changes in the intestinal microbiota of patients with inflammatory bowel disease during an 8-week infliximab infusion cycle

Abstract Background This study investigated changes in the intestinal microbiota during 8-week infliximab maintenance therapy in inflammatory bowel disease (IBD) patients with clinical remission. Microbial compositional differences were analysed according to the trough level of infliximab (TLI) and mucosal healing (MH) status. Methods 16S rRNA gene-based microbiome profiling was performed on 10 and 74 faecal samples from 10 healthy volunteers and 40 adult IBD patients, respectively. All enrolled IBD patients were in clinical remission during infliximab maintenance therapy. To identify changes in the intestinal microbiota, faecal sampling occurred at 1–2 weeks (1W) and 7–8 weeks (7W) after infliximab infusion. TLI was measured by ELISA at 8 weeks immediately before the subsequent infusion; MH was evaluated by endoscopy within 3 months. Results No significant differences were found in microbial composition, species richness, and diversity indices between 1W and 7W samples or in microbial composition and diversity between healthy volunteer and 1W or 7W samples. However, 7W faecal samples from the patients with TLI≥5 μg/ml showed increased species richness compared with TLI&amp;lt;5 μg/ml, and patients with MH showed increased species diversity compared with non-MH. Beta-diversity analysis showed clustering between samples in the MH and non-MH groups. LefSe analysis identified differential expression of Faecalibacterium prausnitzii group between TLI &amp;lt; 5 μg/ml and TLI ≥ 5 μg/ml and MH and non-MH groups. Conclusion There were no significant changes in the intestinal microbiota during an 8-week infliximab infusion cycle in IBD patients with clinical remission; however, microbial composition, species richness, and diversity were associated with TLI and MH status.