Worse outcomes and higher costs of care in fibrostenotic Crohn’s disease: a real-world propensity-matched analysis in the USA

BackgroundPatients with Crohn’s disease (CD) may develop fibrostenotic strictures. No currently available therapies prevent or treat fibrostenotic CD (FCD), making this a critical unmet need.AimTo compare health outcomes and resource utilisation between CD patients with and without fibrostenotic disease.MethodsPatients aged ≥18 years with FCD and non-FCD between 30 October 2015 and 30 September 2018 were identified in the Truven MarketScan Commercial Claims and Encounters Database. We conducted 1:3 nearest neighbour propensity score matching on age, sex, malnutrition, payer type, anti-tumour necrosis factor use, and Charlson Comorbidity Index score. Primary outcomes up to 1 year from the index claim were ≥1 hospitalisation, ≥1 procedure, ≥1 surgery, and steroid dependency (>100 day supply). Associations between FCD diagnosis and outcomes were estimated with a multivariable logistic regression model. This study was exempt from institutional review board approval.ResultsPropensity score matching yielded 11 022 patients. Compared with non-FCD, patients with FCD had increased likelihood of hospitalisations (17.1% vs 52.4%; p<0.001), endoscopic procedures (4.4% vs 8.6%; p<0.001), IBD-related surgeries (4.7% vs 9.1%; p<0.001), steroid dependency (10.0% vs 15.7%; p<0.001), and greater mean annual costs per patient ($47 575 vs $77 609; p<0.001). FCD was a significant risk factor for ≥1 hospitalisation (adjusted OR (aOR), 6.1), ≥1 procedure (aOR, 2.1), ≥1 surgery (aOR, 2.0), and steroid dependency (aOR, 1.7).ConclusionsFCD was associated with higher risk for hospitalisation, procedures, abdominal surgery, and steroid dependency. Patients with FCD had a greater mean annual cost per patient. FCD represents an ongoing unmet medical need.

Emergent immunotherapy approaches for brain metastases

Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.

SURG-03. The effect of surgery on radiation necrosis in irradiated brain metastases: extent of resection and long-term clinical and radiographic outcomes

Objective Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes. Methods A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003–2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups. Results Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (n=42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p&lt;0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p&lt;0.05). There was a trend towards decreased steroid use, from 8mg daily dexamethasone-equivalent (range 2–36) preoperatively to 3mg 12-months postoperatively (range 1–8; p=0.063). Conclusions RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR, and reduced steroid dependency.

Impact of Postoperative Dexamethasone on Survival, Steroid Dependency, and Infections in Newly Diagnosed Glioblastoma Patients

Background We examine the effect of dexamethasone prescribed in the initial 3 postoperative weeks on survival, steroid dependency, and infection in glioblastoma patients. Methods In this single-center retrospective cohort analysis, we electronically retrieved inpatient administration and outpatient prescriptions of dexamethasone and laboratory values from the medical record of 360 glioblastoma patients. We correlated total dexamethasone prescribed from postoperative day (POD) 0 to 21 with survival, dexamethasone prescription from POD30 to POD90, and diagnosis of an infection by POD90. These analyses were adjusted for age, KPS, tumor volume, extent of resection, IDH1/2 tumor mutation, tumor MGMT promoter methylation, temozolomide and radiotherapy initiation, and maximum blood glucose level. Results Patients were prescribed a median of 159 mg [109-190] of dexamethasone cumulatively by POD21. Every 16mg increment (4mg every 6 hours/day) of total dexamethasone associated with a 4% increase in mortality (95% confidence interval, CI, 1–7%, P&lt;0.01), 12% increase in the odds of being prescribed dexamethasone from POD30-POD90 (95% CI 6–19%, P&lt;0.01), and a 10% increase in the odds of being diagnosed with an infection (95% CI, 4–17%, P&lt;0.01). Of the 175 patients who had their absolute lymphocyte count measured in the preoperative week, 80 (45.7%) had a value indicative of lymphopenia. In the POD1-POD28 period, this proportion was 82/167 (49.1%). Conclusions Lower survival, steroid dependency, and higher infection rate in glioblastoma patients associated with higher dexamethasone administration in the initial 3 postoperative weeks. Nearly half of the glioblastoma patients are lymphopenic preoperatively and up to one month postoperatively.

Urinary Tetrahydrocortisol/Tetrahydrocortisone Ratio at Early Postnatal Period Predict Steroid Dependency and Neonatal Condition in Preterm Infant

Insufficient adrenal function in preterm infants affects poor neonatal outcome, owing to the immaturity of their adrenal enzyme. While 11β-hydroxysteroid dehydrogenase (11βHSD) type 1 and type2 act as gatekeepers for cell steroid action. This study aimed to investigate the effects of early postnatal urinary tetrahydrocortisol/tetrahydrocortisone (F/E) ratio, used as an alternative indicator of 11βHSDs activity, in preterm infants on their subsequent clinical course. In 80 preterm infants of ≤ 34 weeks gestational age admitted to our hospital, urinary F/E ratio was measured within 24 hours of birth. Furthermore, the relationship between this ratio and neonatal outcomes was estimated. Univariate analysis revealed that the high F/E ratio group had significantly higher morbidity in terms of duration of ventilatory support for more than 14 days, hypotension requiring inotropes and hydrocortisone, and symptomatic patent ductus arteriosus. On multivariate analysis, the incidence of hypotension requiring hydrocortisone was higher in the high F/E group, despite the absence of elevated dehydroepiandrosterone, a precursor of cortisol.Conclusion: The urinary F/E ratio in the early postnatal period in preterm infants may contribute to the understanding of the pathogenesis of infant condition after birth by estimating the amount of local steroid action in the organs.

P464 Steroid dependency in patients with Ulcerative Colitis treated with advanced therapies in a German real-world-setting

Background An important treatment goal in Ulcerative Colitis (UC) is a long-lasting corticosteroid (CS)-free remission. Avoidance of steroid dependency in these patients is essential as chronic CS use is known to be associated with an increased risk for multiple severe adverse events. This study aimed to identify CS dependency in patients with moderate to severe UC treated with advanced therapies. Methods This German claims data analysis includes adult patients with ≥2 outpatient diagnoses and/or one inpatient diagnosis for UC (ICD-10: K51) in whom an advanced therapy (anti-TNF agent, vedolizumab or tofacitinib) was initiated between 01/01/2015–30/06/2019. CS dependency was indicated by ≥2 prescriptions of systemic CS and/or oral budesonide within a median follow-up of 23.4 months. Prior CS use was evaluated by outpatient prescriptions observed in a 12-months baseline period. Costs were assessed until the end of the study period or loss to follow-up considering all-cause expenses for inpatient and outpatient visits, and approximated indirect cost related to sick-leave days. Exceeding the recommended dose in maintenance therapy by more than 150% was rated as an escalation of therapy. Time to the therapy discontinuation, escalation or first UC-related hospitalization from start of index therapy were estimated using Kaplan-Meier analysis. Results Of 574 included UC patients with a new advanced therapy, 252 (43.9%) received ≥2 prescriptions of CS while on treatment with advanced agents in the observation period up to 24 months. Altogether, 496 patients (86.4%) had prior experience with CS in the 12-months baseline-period. Among patients with ≥2 CS prescriptions, 47.0% had switched their index therapy to another advanced agent after 24 months (31.2% without CS dependency). Median time to therapy discontinuation was 17.3 months in CS-dependent patients; and 19.3 months in those without CS dependency (p = 0.639). There were no differences between naïve or advanced therapy experienced patients, but with clearly more discontinuations in patients with previously more than 1 advanced therapy (p&lt;0.001). CS-dependent patients were more likely to require dose escalation/UC-related hospitalization within the first two years after treatment start (26.7% vs. 16.1%; p = 0.018/ 44.1% vs. 26.6%; p = 0.048; Figure 1). Total cost per patient-year was significantly higher in patients with than without CS dependency (40,884 € vs. 37,449 €; p &lt; 0.001). Conclusion Most UC patients starting new advanced therapies were previously treated with CS, and more than two-fifths continue to be CS dependent even after starting such a therapy. More effective therapies are needed to achieve CS-free remission.

Association between antidepressant medication use and steroid dependency in patients with ulcerative colitis: a population-based study

BackgroundAnimal studies indicate a potential protective role of antidepressant medication (ADM) in models of colitis but the effect of their use in humans with ulcerative colitis (UC) remains unclear.ObjectiveTo study the relationship between ADM use and corticosteroid dependency in UC.DesignUsing the Clinical Practice Research Datalink we identified patients diagnosed with UC between 2005 and 2016. We grouped patients according to serotonin selective reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) exposure in the 3 years following diagnosis: ‘continuous users’, ‘intermittent users’ and ‘non-users’. We used logistic regression to estimate the adjusted risk of corticosteroid dependency between ADM exposure groups.ResultsWe identified 6373 patients with UC. Five thousand two hundred and thirty (82%) use no ADMs, 627 (10%) were intermittent SSRI users and 282 (4%) were continuous SSRI users, 246 (4%) were intermittent TCA users and 63 (1%) were continuous TCA users.Corticosteroid dependency was more frequent in continuous SSRI and TCA users compared with non-users (19% vs 24% vs 14%, respectively, χ2 p=0.002). Intermittent SSRI and TCA users had similar risks of developing corticosteroid dependency to non-users (SSRI: OR 1.19, 95% CI 0.95 to 1.50, TCA: OR 1.14, 95% CI 0.78 to 1.66). Continuous users of both SSRIs and TCAs had significantly higher risks of corticosteroid dependency compared with non-users (SSRI: OR 1.62, 95% CI 1.15 to 2.27, TCA: OR 2.02, 95% CI 1.07 to 3.81).ConclusionsContinuous ADM exposure has no protective effect in routine clinical practice in UC and identifies a population of patients requiring more intensive medical therapy. ADM use is a flag for potentially worse clinical outcomes in UC.

P609 Impact of accessibility of medical care and socioeconomic class on outcomes of IBD – a nationwide population study

Background Despite ongoing improvements in Inflammatory Bowel Disease (IBD) therapeutics, timely access to quality medical care likely impacts patient outcomes. Physical distance from specialty care and socioeconomic status (SES) may impact quality of care. In a nationwide population study we aimed to assess the impact of patient location and SES on IBD outcomes. Methods This Epi-IIRN project utilized a meta-database incorporating patient data of all four health maintenance organisations (HMO) in Israel, representing 98% of the population. All patients identified on the incidence cohort were followed from diagnosis until end of 2018. Regions in Israel were defined as central (coastal plain and Jerusalem corridor), northern region and southern region. SES class were defined by postcode as per Israel bureau of statistics data from SES 1 (lowest) to SES 4 (highest). Primary outcome was steroid dependency, with secondary outcomes of biologic therapy use during first year of diagnosis, surgery, gastroenterology visits, hospitalizations and mortality. Analysis was performed separately for Crohn’s disease (CD) and ulcerative colitis (UC). Results A total of 30,167 IBD patients (16,936 (56%) CD and 13,231 (44%) UC) were included: 74% of patients were in central region, 12% southern region and 14% northern region. 21% were in SES class 1 and 12% in SES 4. In CD, lower SES was associated with higher steroid dependency (37% vs 30%, p=0.002), higher surgery rates (21% vs 12%, p&lt;0.001), more hospitalizations (2.4 vs 1.1, p&lt;0.001), more emergency department (ER) visits (2.9 vs 1.9, p&lt;0.001) and higher mortality (3.3% vs 2.5%, p=0.03). Regarding region, steroid dependency, hospitalization rate, ER visits and surgery rate were all lower in central regions compared to both northern and southern region (p&lt;0.001 for both central vs northern, and central vs southern regions). Similarly, gastrointestinal specialized clinic visits were more frequent in central regions (p=0.01). In UC, lower SES was associated with lower frequency of gastrointestinal clinic visits (5.0 vs 8.5, p&lt;0.001). This was associated with more hospitalizations (1.6 vs 0.7, p&lt;0.001), ER visits (2.1 vs 1.6, p=0.002), surgeries (7.6% vs 5.0%, p=0.014) and higher mortality (5.1% vs 4.2%, p=0.026). By region, gastrointestinal clinic visits were more frequent, and ER visits, hospitalizations (all p&lt;0.001) and surgeries (p=0.001) were all lower in central compared to both northern and southern regions. Conclusion In this nationwide analysis we show deleterious impact of both lower SES and peripheral residence on outcomes of CD and UC. Policy makers should consider these data to facilitate improved access to medical care and maximize IBD outcomes in a standardized way.

A178 USTEKINUMAB FOLLOWING PRIMARY ANTI-TNF FAILURE AND SECONDARY LOSS OF RESPONSE TO VEDOLIZUMAB IN AN ADOLESCENT WITH ULCERATIVE PANCOLITIS

Background Infliximab is, to date, the only biologic therapy approved for the treatment of ulcerative colitis (UC) in paediatric patients. Although often effective, primary mechanistic failure is more common in UC than in luminal inflammatory paediatric Crohn’s disease (CD). Alternate pathway biologics, specifically vedolizumab (anti-α4β7 integrin) and ustekinumab (anti-interleukins 12/23) are increasingly used in adults with UC. Emerging data from head to head trials of biologics and network meta-analyses of placebo-controlled trial data are being used to guide choice and sequencing of therapeutic agents. Even among adults with UC data concerning combination biologics are very limited. Aims To report the outcomes of addition of ustekinumab to vedolizumab in a patient with steroid dependent colitis, previous primary non-response to infliximab and secondary loss of response to vedolizumab monotherapy. Methods Case report Results A 17 years old girl was hospitalized with acute severe colitis (PUCAI 85) developing as oral prednisone was tapered below 30 mg daily despite ongoing intensified vedolizumab therapy (300 mg q4 weekly) and per rectal steroids. First presentation 2 years earlier with UC pancolitis, responsive to oral prednisone, maintained on oral 5-ASA until first exacerbation 8 months later. Responsive then to IV steroids, but unable to maintain steroid-free remission despite intensified infliximab with therapeutic levels. Vedolizumab initiated in setting of primary mechanistic anti-TNF failure. Steroid-free clinical remission for 7 months of q 8 weekly dosing with normalization of fecal calprotectin (16, 115 µg/g) when symptoms recurred and persisted despite shortening of vedolizumab dosing interval to 4 weeks. Vedolizumab level 34 µg/mL. Symptomatic response to oral prednisone 40 mg, but unsustained with tapering. Hospitalized with up to 10 bloody stools per day, nocturnal stools, abdominal pain and anemia requiring blood transfusion. High doses of IV steroids were given with slow response. Colectomy refused by family. IV ustekinumab 390 mg given. Vedolizumab continued q 8 weekly in view of prior responsiveness. Ustekinumab subcutaneous maintenance therapy initiated at week 8 and continuing q 4 weekly (levels 3.3 mg/L). Oral prednisone tapered and discontinued. At 5 months post ustekinumab initiation, patient is in steroid-free clinical remission (PUCAI 0). Fecal calprotectin has declined from &gt;1800 to 723 µg/g. Conclusions In this patient with UC and primary failure of anti-TNF, ustekinumab has demonstrated short-term efficacy in alleviating steroid-dependency. The contribution of continued vedolizumab, to which there had previously been secondary loss of response, is unknown. Nevertheless, the safety profile of vedolizumab allows it to be combined with other therapies in selected treatment-refractory patients. Funding Agencies None