Ustekinumab Dose Research Articles

P261 Predictors and outcomes of ustekinumab dose escalation to every 4 or every 6 weeks in ulcerative colitis: a multicenter cohort study in the United States

Abstract Background Patients with ulcerative colitis (UC) on ustekinumab (UST) therapy may have suboptimal response to standard every 8 week (q8w) dosing. Empiric dose escalation to q4w or q6w is common, but the efficacy of these strategies are unknown in UC. We performed a multicenter cohort study to identify predictors and outcomes of UST dose escalation in UC. Methods This retrospective cohort study included adults initiating UST for UC (ICD-10-CM 51x) at three academic medical centers in the United States 1/1/2016-11/1/2021. Patients with prior colectomy were excluded. Disease activity was assessed using the 9-point Mayo score or simple clinical colitis activity index (SCCAI) in electronic health records. Independent variables included demographics, UC duration, extraintestinal manifestation, medication/substance use history, endoscopic extent/severity, reason for escalation, intravenous (IV) reinduction, dose interval, albumin, C-reactive protein, and bowel frequency. The primary outcome was steroid-free clinical remission (SCCAI/Mayo <3 points) 12–16 weeks after escalation. Secondary outcomes were clinical response (reduction in SCCAI/Mayo by ≥3 points from baseline) at 12–16 weeks and time to escalation. Additional endpoints included endoscopic response, failure within 16 weeks (treatment discontinuation or colectomy), improvement in fecal calprotectin, UC hospitalisation, and adverse events. Multivariable logistic and cox regression were used to identify factors associated with remission and time to escalation, respectively. Results 108 UC patients initiated UST: 91.7% had prior anti-TNF exposure and 57.4% were taking oral steroids (Table 1). 39.6% (40/101 with data) achieved remission 12–16 weeks after induction. 42.6% (46/108) were escalated to q4w (n=33) or q6w (n=13) after median of 95 days (IQR 65–208 days) primarily for no/minimal response to induction (22/46) or loss of response (20/46) (Fig 1A). 55.0% (22/40 with data) achieved remission at 12–16 weeks, 67.5% (27/40) had response, 56.3% (9/16 with data) had endoscopic response (Table 2), and 30.0% (12/40) had treatment failure (Fig 1B). 10.0% (4/40) were hospitalised after median of 80 days and 5.0% (2/40) had adverse events (urinary tract infection and C. difficile infection). After multivariable analysis, lack of response to induction was inversely associated with remission after escalation. Bowel frequency and >2 prior biologics were associated with time to escalation (Table 3). Conclusion UST dose escalation resulted in clinical remission in >50% of UC patients and was more effective in those with loss of response compared to no/minimal response after induction. Prospective studies are needed to identify UC subpopulations that will benefit from various dosing strategies of UST.

P508 Dose adjustment in patients with moderate to severe ulcerative colitis: results from year 3 of the UNIFI maintenance study long-term extension

Abstract Background The UNIFI randomized-withdrawal maintenance study and long-term extension (LTE) evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment through Week (Wk) 152 of the long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 weeks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST patients who completed wk44 entered the LTE. PBO patients were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, patients in the LTE were eligible to receive dose adjustment starting at Wk 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Patients in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Patients were assessed for symptomatic remission, partial Mayo scores, and inflammatory markers ≥16 wks after dose adjustment. Results Overall, 60 patients (42.6%) in the q12w group and 40 patients (28.0%) in the q8w group underwent dose adjustment (or sham dose adjustment) prior to Wk 156 of the LTE; 51 and 39 patients in each group, respectively, had dose adjustment at Wk 136 or before, providing≥16 wks of data after dose adjustment (Table). At the first visit ≥16 weeks after dose adjustment, 70.6% of patients who adjusted from q12w to q8w and 61.5% who sham dose adjusted from q8w to q8w were in symptomatic remission. At the time of dose adjustment, 27/51 patients (52.9%) in the q12w group and 25/39 patients (64.1%) in the q8w group were in symptomatic remission. Of those who were in symptomatic remission at the time of dose adjustment, the majority (81.5% and 68.0%, respectively) were maintained in symptomatic remission at the first visit ≥16 wks after dose adjustment. Of those who were not in symptomatic remission at the time of dose adjustment, 58.3% and 50.0%, respectively, were in symptomatic remission at the first visit ≥16 wks after dose adjustment. Mean partial Mayo scores and CRP levels decreased after dose adjustment (Table). Conclusion Patients may benefit from UST dose adjustment to q8w.

P412 Effectiveness of ustekinumab in fistulising perianal Crohn′s disease refractory or intolerant to anti-TNF

Abstract Background The management of fistulising perianal Crohn′s disease (pCD) is a challenging problem for patients and physicians. New therapeutic alternatives are needed, particularly in anti-TNF refractory patients. Data regarding ustekinumab (UST) effectiveness in pCD are scarce. Our aim was to evaluate the clinical and radiologic effectiveness of UST in pCD patients refractory or intolerant to anti-TNF. Methods We conducted a multi-center retrospective observational study. All patients with anti-TNF refractory pCD treated with UST were evaluated. Demographic and clinical variables including concomitant drugs were registered. Clinical response was evaluated at 16 weeks and 12 months and was defined as a reduction of 50% of draining fistulas or a marked reduction in fistula drainage. In patients with a magnetic resonance imaging (MRI) before and after treatment initiation, radiologic response was defined according to Ng Score (healed, partial response, unchanged, deterioration). Results Thirty-two patients were included, 68.8% female, median age 44,11 (IQR 36.28-48.56). Median time from diagnosis to UST initiation was 12.94 years (IQR 7.52-19.52), 90.6% had received previously 2 anti-TNF (37.5% also vedolizumab) and 46.9% had more than 2 fistulas. In 22 patients (68.8%) pCD was the main indication for UST treatment while in the remaining 31.2% the main indication was luminal disease. Fifteen patients (46.9%) received antibiotics at the initiation of UST, 8 (25%) combo therapy with thiopurines and 21 (65.6%) had setons. Patients received a 6mg/kg IV dose and 87.5% received 90mg/8 week SQ for maintenance. Dose intensification was needed in 20 patients (62.5%) at a median of 13 months (IQR 8.00-19.5). Fifteen patients (46,9%) achieved clinical response at week 16, while 18/30 (60%) had clinical response at 12 months (three of them were in clinical remission). Nineteen patients (59,4%) had an MRI performed pre and post-treatment at a median of 15 months (IQR 10-19). 10/19 patients (52.6%) achieved a radiological response although no patient had all fistulas healed. In the multivariate analysis the only factor associated with clinical response at 12 months was the presence of setons at UST initiation (OR 7.0; IC95% 1.3-37.9). There were no factors significantly associated with radiological response or clinical response at week 16. Four patients experienced adverse effects (three perianal abscesses and one transient skin rash). Conclusion Ustekinumab was effective in achieving clinical and radiological response in anti-TNF-refractory fistulising pCD patients, although clinical and radiological remission was rare. Most patients needed UST dose intensification in this highly refractory cohort. Adverse effects were infrequent, mainly perianal abscesses.

Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn’s disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients.Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient’s clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab.Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment.Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry.

BackgroundThe development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice.AimsTo evaluate the durability, effectiveness and safety of ustekinumab in UC in real-life.MethodsPatients included in the prospectively maintained ENEIDA registry who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at week 16.ResultsA total of 95 patients were included. At week 16, 53% of patients had response (including 35% of patients in remission). In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at weeks 24 and 52, respectively. Thirty-six percent of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection.ConclusionsUstekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn’s disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn’s disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017–2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification. Trial registration EUPAS30920

Predictors and Outcomes of Ustekinumab Dose Intensification in Ulcerative Colitis: A Multicenter Cohort Study

Ustekinumab has been shown to be effective for the treatment of ulcerative colitis (UC); however, >40% of patients have suboptimal clinical response after induction and maintenance dosing every 8 weeks.1,2 The best management approach for these patients is unclear. Many undergo empiric dose intensification to every 4 weeks or every 6 weeks, a nonstandardized decision because of limited data supporting therapeutic drug monitoring of ustekinumab.3 In Crohn's disease, approximately 50% of patients undergo ustekinumab dose intensification, which seems to be effective based on prior work from our group and others.4-8 However, similar data in UC are lacking. In this real-world multicenter cohort study, we sought to identify predictors and outcomes of ustekinumab dose intensification in UC.

Ustekinumab for Ulcerative Colitis

Ustekinumab for Ulcerative Colitis

MINIMAL INVASIVE MANAGEMENT OF PEDIATRIC CROHN’S ANORECTAL STRICTURE, LESS IS MORE

Abstract Background Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy. Methods An institutional review board-approved retrospective review was performed using electronic health records. Three patients with ileocolonic CD and perianal involvement with symptomatic ARS were identified. All patients were treated with serial rectal dilations under general anesthesia using Hegar dilators. Results All patients are currently asymptomatic at follow-ups ranging from 1 to 3.5 years since the last dilation. Patient demographics and details of ARS management are presented in Table 1. All patients tolerated the procedures well and did not experience complications such as perforation, sepsis, or fecal incontinence. Rectal biopsy in each patient showed active inflammation, suggesting type 1 stricture according to the Hughes-Cardiff Classification (vs. type 2 fibrotic stricture). Patient 1 experienced 6 recurrences, each managed with an average of 2 dilations until disease control was established with ustekinumab (USK) and eventually vedolizumab (VDZ). She underwent ileocecal resection three years after the final dilation. Patient 2 underwent ileocecal resection immediately following the first series of dilations. He later experienced one stricture recurrence at 2 years, which was managed with one dilation and increased USK dosing frequency. Patient 3 received steroid suppositories prior to dilation and has been self-dilating at home. He has had no recurrences requiring operative dilation. Self-dilation was not feasible in patients 1 and 2. Conclusion Inflammatory anorectal stricture associated with perianal Crohn disease in pediatric patients can be managed successfully with dilation until disease control with biologic therapy. Recurrences of stricture can also be managed with dilation and modification of biologic therapy. If tolerated, self-dilation may reduce recurrence. Background Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy. Crohn’s rectal stricture pre and post dilation

Characteristics of patients with psoriatic arthritis treated with ustekinumab. Evidence from real-life clinical practice

Introduction. Psoriatic arthritis (PsA) is a chronic immunoinflammatory disease characterised by involvement of the skin, nail plates, joints, spine and entheses in the inflammatory process. The IL-12/IL-23 inhibitor ustekinumab (UST) is increasingly being used in psoriasis (Ps) and PsA.Aim of the study. To analyze patients with PsA who were under inpatient treatment in the V.A. Nasonova Scientific Research Institute of Rheumatology and Radiology and who were prescribed UST during the period from 2018 to 2020.Material and methods. UST was administered to 17 patients with PsA (9 women and 8 men), mean age was 46.4 ± 11.3 years. Duration of PsA course was 11 ± 10.5 years. Patients underwent clinical, laboratory and instrumental examination, BSA and PASI, DAPSA and BASDAI indices were determined.Results. Patients predominantly had widespread Ps (BSA 18.2 ± 15.9%). Erosive arthritis was present in 94.1% of patients, and sacroiliitis was detected in 100% of patients. PsA activity was high (DAPSA = 44.9 ± 20.9, BASDAI = 6.2 ± 1.5).94% of patients had two or more comorbidities. Circulatory system diseases were observed in 82.4% of patients, liver diseases in 29.5%, gastrointestinal diseases in 47%, endocrine system diseases in 17.6%, viral hepatitis C in 23.5%, latent tuberculosis infection in 17.6%, and joint surgery was performed in 11.2% of patients. The clinical example presented in the article demonstrates good tolerability of UST in a patient with PsA with a number of comorbidities and the possibility to increase the dose of UST from 45 to 90 mg in case of ineffective therapy.Conclusions. The safety profile of UST is good, and it can be administered to patients with cardiovascular diseases, obesity, various infections, including latent tuberculosis, etc.

Ustekinumab pharmacokinetics after subcutaneous administration in swine model.

BackgroundDue to multiple similarities in the structure and physiology of human and pig skin, the pig model is extremely useful for biological drug testing after subcutaneous administration. Knowledge of the differences between subcutaneous injection sites could have a significant impact on the absorption phase and pharmacokinetic profiles of biological drugs.ObjectivesThis study aimed to analyze the impact of administration site on pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab in pigs. Drug concentrations in blood plasma were analyzed by enzyme-linked immunosorbent assay. Pharmacokinetic analyses were performed based on raw data using Phoenix WinNonlin 8.1 software and ThothPro v 4.1.MethodsThe study included 12 healthy, female, large white piglets. Each group received a single dose of ustekinumab given as a 1 mg/kg subcutaneous injection into the internal part of the inguinal fold or the external part of the inguinal fold.ResultsThe differences in absorption rate between the internal and external parts of the inguinal fold were not significant. However, the time of maximal concentration, clearance, area under the curve calculated between zero and mean residence time and mean residence time between groups were substantially different (p > 0.05). The relative bioavailability after administration of ustekinumab into the external part of the inguinal fold was 40.36% lower than after administration of ustekinumab into the internal part of the inguinal fold.ConclusionsHealthy breeding pigs are a relevant model to study the pharmacokinetic profile of subcutaneously administered ustekinumab.

Issue Highlights

Although the introduction of biologics for the treatment of Crohn’s in 1998 revolutionized our approach to this disease, primary non-response and secondary loss of response remain vexing problems for a large subset of patients in clinical practice. For anti-TNF agents, common reasons for loss of response include subtherapeutic drug concentrations and development of neutralizing anti-drug antibodies. Therapeutic drug monitoring, dose escalation and interval shortening are approaches with demonstrated effectiveness recapturing response to these agents and are commonly employed in clinical practice. 1 Papamichael K. Cheifetz A.S. Melmed G.Y. et al. Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3 Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Shortening the dose interval or dose intensification for Vedolizumab has also been shown to permit recapturing of response in some patients, 2 Peyrin-Biroulet L. Danese S. Argollo M. et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with crohn's disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019; 17: 838-846.e2 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar but whether this approach can be extrapolated to Ustekinumab remains unclear. This retrospective study by Ollech et al 3 Ollech J.E. Normatov I. Peleg N. et al. Effectiveness of Ustekinumab dose escalation in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2021; 19: 104-110 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar is the first to evaluate real-world effectiveness of interval shortening from 8- to 4-week dosing for Ustekinumab. The authors describe pre- and post-dose escalation parameters including Harvey Bradshaw Index (HBI), C-reactive protein (CRP), and fecal calprotectin for a subset of 110 patients not responding to Ustekinumab every 8 weeks. Although not all patients in the subset had all parameters pre- and post-dose increase, of the 78 patients (71%) with pre-and post-HBI metrics, the median HBI decreased from 4.5 to 3 (P = .002). Of 60 patients (55%) with CRP measurements, median CRP decreased from 8 mg/L to 3 mg/L (P = .031). Among patients with HBI >4, CRP ≥5 mg/L, fecal calprotectin >250 μg/g, or endoscopic evidence of active disease, 28% achieved clinical remission (HBI<4), 22% normalized CRP, and 36% endoscopic remission with a median follow up of 9 months post-dose increase. 38% of patients on steroids were able to discontinue, and 45% with active perianal disease reported resolution within 6 months of dose-escalation. Twenty-three patients (20.9%) discontinued therapy following dose escalation, most (78%) due to lack of response; only 1 due to side effects (rash). This is the first study to demonstrate improvement in objective measures of Crohn’s disease activity with dose-intensification of Ustekinumab from 8- to 4-week intervals. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn’s DiseaseClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewA subset of patients with Crohn’s disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses. Full-Text PDF Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis–Related, Child–Pugh A CirrhosisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewFactors that affect outcomes of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use of antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis. Full-Text PDF Intragastric Balloon Placement Induces Significant Metabolic and Histologic Improvement in Patients With Nonalcoholic SteatohepatitisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewObese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH. Full-Text PDF Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular CarcinomaClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewUltrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. Full-Text PDF

P028 Outcomes of Standard and Intensified Dosing of Ustekinumab for Chronic Pouch Disorders

BACKGROUND: Patients with chronic antibiotic-refractory pouchitis and Crohn's disease (CD) of the pouch are often treated with biologic agents. Data regarding the efficacy of ustekinumab therapy dosed every 8 weeks (q8w) and intensified dosing to q6w or q4w for these conditions is limited. We sought to assess outcomes of standard and intensified ustekinumab dosing and identify factors associated with clinical response among patients with chronic pouch disorders. METHODS: This retrospective cohort study included adults initiated on ustekinumab for chronic pouch disorders between January 1, 2016 and March 1, 2020. Electronic health records were reviewed to obtain demographic and clinical data. The primary outcome was physician-reported clinical response 2-4 months after ustekinumab initiation (q8w) or dose intensification (q6w or q4w). The secondary outcome was time to dose intensification. Additional outcomes included pouch excision with permanent ileostomy, improvement in the 6-point clinical subscore of the pouchitis disease activity index (PDAI), IBD-related hospitalization, improvement in severity/extent of inflammation on pouchoscopy, and discontinuation of chronic antibiotics. Univariable logistic and cox regression were used to identify characteristics associated with primary and secondary outcomes, respectively. RESULTS: 46 patients were initiated on ustekinumab for pouchitis (n = 6), cuffitis (n = 4), or CD of the pouch (n = 36). Outcomes after initiation were as follows (denominators vary due to missing data or insufficient follow-up time): 80.4% (37/46) of patients had a physician-reported clinical response at 2-4 months, 50.0% (23/46) underwent dose intensification after a median of 223 days, 8.7% (4/46) had a permanent ileostomy after a median of 571.5 days, 59.1% (26/44) had an improvement in PDAI clinical subscore at 2-4 months, 16.2% (6/37) were hospitalized within 12 months, 53.6% (15/28) of those who underwent pouchoscopy after initiation had improvement in pouch inflammation, and 30.8% (4/13) of patients on chronic antibiotics discontinued antibiotics within 12 months. Logistic regression demonstrated that female sex (OR 10.5; 95% CI 1.2-92.7; P = 0.03) and pouch fistula (OR could not be calculated; 37.8% clinical response vs. 0.0% no clinical response; P = 0.04 by Fisher's exact test) were positively associated with clinical response after initiation and cannabis use (OR 0.15; 95% CI 0.03-0.75; P = 0.02) was inversely associated with clinical response. Cox regression demonstrated that younger age at IBD diagnosis (HR 0.94; 95% CI 0.90-0.99; P = 0.01) and younger age at initiation (HR 0.96; 95% CI 0.92-0.99; P = 0.04) were associated with shorter time to dose intensification. After dose intensification to q4w or q6w, there were similar rates of clinical response at 2-4 months (61.9% q4w, 66.7% q6w), improvement in pouchoscopy (70.0% q4w, 75.0% q6w), and improvement in PDAI clinical subscore (47.6% q4w, 46.7% q6w) at 2-4 months. One patient experienced an adverse event (acneiform reaction), leading to ustekinumab discontinuation 807 days after dose intensification. On logistic regression analysis, no baseline characteristics were significantly associated with clinical response after dose intensification. CONCLUSION: While ustekinumab was effective for the majority of patients in our cohort, nearly 50% ultimately required dose intensification, which was effective in recapturing response for most patients. Larger, prospective studies are needed to determine the optimal subpopulations in which to employ various dosing strategies of ustekinumab for chronic pouch disorders.

P019 Covid-19 Infection in a Patient with Crohn's Disease Under Treatment with Ustekinumab - Case Report

CASE: We report a case of a 44-year-old patient with ileocolonic Crohn's disease, infected with SARS-Cov-2 and, on treatment with ustekinumab for six months. The patient has been treated for Crohn's disease since 2002. Ustekinumab was prescribed after the failure of treatment with infliximab and adalimumab six months ago. In May 2020, she presented headache, coryza, general malaise, and a temperature of 37.7oC, which persisted for two days. She sought an emergency room for investigation and presented the following lab tests results: Hb = 14.9g/dl; Ht = 44%; Total leucocytes = 8400/mm3; Lymphocytes = 15% (normal range 20-45%); Platelets count = 357.000/mm3; CPR = 20mg/L (normal value < 500ng/mL), oxygen saturation = 97%. Chest tomography showed ground-glass peripheral pulmonary opacities with impairment of less than 25%. Given Covid-19 suspicious, rt-PCR for SARS-Cov-2 was collected and the result was positive. She was discharged to her home with symptomatic pills and azithromycin 500mg/day for 5 days. In the following days, she presented diarrhea (8x/day), nausea, vomiting, and returned to the emergency room for intravenous medication and hydration. After this treatment, she was discharged again to her home. There was an improvement in symptoms, but diarrhea persisted for 8 days. The next maintenance dose of ustekinumab was suspended for 15 days. After this period, she collected a control rt-PCR for SARS-Cov-2 that resulted negative and, returned to use biologic therapy without presenting any complication. In this case, there was a good recovery of Covid-19 even during the use of ustekinumab. The possibility of performing rt-PCR and monitoring signs and symptoms of the disease, allowed the period of active infection to be properly controlled. Additionally, biological therapy could also be promptly resumed without jeopardizing the treatment of Crohn's disease.

Predictors of Ustekinumab Failure in Crohn's Disease After Dose Intensification.

Many patients with Crohn's disease (CD) who lose response to the standard ustekinumab dose interval of every 8 weeks (q8w) undergo dose intensification to q4w or q6w. However, baseline factors that predict success or failure after dose intensification are unknown. We sought to identify predictors of failure of ustekinumab after dose intensification for patients with CD. This was a retrospective cohort study of adult CD patients undergoing ustekinumab dose intensification at a tertiary referral center between January 1, 2016, and January 31, 2019. Electronic health records were reviewed to obtain patient demographics, CD history, and laboratory data. The primary outcome was failure to achieve corticosteroid-free remission (Harvey-Bradshaw Index <5) within 12 months after intensification. The secondary outcome assessed was time to new biologic therapy after dose intensification. We used multivariable logistic regression and Cox regression to identify predictors of these outcomes. We included 123 patients who underwent ustekinumab dose intensification to q4w (n = 64), q5w (n = 1), q6w (n = 55), or q7w (n = 3). Multivariable logistic regression demonstrated that perianal disease, Harvey-Bradshaw Index, and opioid use at time of intensification were associated with failure to achieve remission. Cox regression demonstrated that perianal disease and corticosteroid use at time of intensification were associated with shorter time to a new biologic. Perianal disease, Harvey-Bradshaw Index, current opioid use, and current corticosteroid use are associated with ustekinumab failure after dose intensification in CD. Larger, prospective studies are needed to corroborate these findings and guide therapeutic strategies for patients who lose response to standard ustekinumab dosing.

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220. To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90mg every 12weeks [q12w], and 143 received ustekinumab 90mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12weeks and at each dosing visit after unblinding. Safety was evaluated throughout. Among all patients randomised in maintenance, symptomatic remission rates (stool frequency=0/1; rectal bleeding=0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. The efficacy of ustekinumab in patients with UC was sustained through 92weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

S3210 Assessment of Factors Which May Predict Crohn’s Disease Relapse in Patients Initiating Ustekinumab Therapy

INTRODUCTION: Ustekinumab is a biologic agent, acting against the p40 subunit of IL 12 and IL 23, approved for use in Crohn’s disease (CD). Currently, ustekinumab is approved for every 8 week dosing following initiation. However, we have clinically observed the need for every 4 week dosing, in a cohort of patients not achieving control with every 8 week administration. Of note, such a subset of CD patients was not assessed in the UNITI trial. The aim of our study was to identify patient or clinical factors that could indicate the need for a shorter ustekinumab dosing interval to obtain and maintain remission of CD. METHODS: The pharmacy database was searched for all patients initiating ustekinumab for histologically confirmed CD. Patients were then divided into 2 groups following initiation based on occurrence of next dose, either standard schedule (8 weeks after initial dose) or early administration (4 weeks following). Data collected for all included demographic information, smoking status, extent of disease and disease duration. Stepwise logistic regression was used to identify predictors for early dosing. Potential predictors not identified by the logistic model were forced in. Beta coefficients/odds ratios and 95% confidence intervals were calculated to estimate the magnitude of the effect. RESULTS: A total of 57 CD patients were eligible for study. The majority of patients overall were female (68%) and non-Hispanic white (52%). A total of 44 patients were in the standard group and 13 patients were in the early administration group. No difference in age, gender, race, smoking status or disease duration was present between groups. Colonic CD disease extent was significantly different between standard and early groups (one colonic segment involved in 36.4% of standard vs 84.6% of early patients, P < 0.003). We further forced in age, sex, race, smoking status, and duration of disease as likely to impact occurrence of early ustekinumab dosing. Again, only extent of disease on colonoscopy showed a statistically significant result (OR 9.56, CI 1.41–64.88, P < 0.01). CONCLUSION: Extent of colonic disease may identify those CD patients at risk for earlier than 8 week dosing following initiation of ustekinumab. We identified that patients with one colonic segment involvement have higher odds to be on early administration than those that have multiple colonic segment involvement. Further evaluation of this clinical phenomenon is warranted to completely understand ustekinumab use in CD.

S0733 Factors Associated With Ustekinumab Dose Escalation in Patients With Crohn's Disease

INTRODUCTION: Ustekinumab (UST) is a monoclonal antibody which inhibits both IL-12 and IL-23 activity and was approved for treatment of Crohn's disease (CD) in 2016. The current approved dosing is an initial intravenous weight-based loading dose followed by 90 mg subcutaneous maintenance injections every 8 weeks. Yet, patients frequently require dose escalation, most commonly to every 4 or 6 weeks. However, reasons for UST dose escalation and to which interval are poorly understood. METHODS: Retrospective cohort study of adult patients with CD who were treated with UST and underwent dose escalation between 1/1/2016 and 1/31/2019 at a tertiary referral center. Electronic health records were manually reviewed for demographic data, CD history, UST serum concentrations within 3 months prior to escalation and to identify primary reason for dose escalation. RESULTS: We identified 238 patients on UST for CD. Among these patients, 123 (51.7%) underwent escalation to every 4 (n = 64), 5 (n = 1), 6 (n = 55) or 7 (n = 3) weeks. UST serum concentrations were measured in 18/238 (14.6%) patients within 3 months prior to dose escalation with mean of 2.0 ug/ml and 1.3 ug/ml in patients escalated to 4 or 6 weeks, respectively (P = 0.54). Of the 123 patients, a total of 85 patients (69.1%) were escalated due to persistent clinical disease activity with Harvey Bradshaw Index (HBI) of 5 or greater. Among the 38 patients with HBI <5, primary reasons for escalation were as follows; early symptom recurrence (n = 10), concurrent corticosteroid use (n = 8), evidence of inflammation on endoscopy (n = 8), low UST drug concentrations (n = 3), elevated fecal calprotectin (n = 3), radiographic evidence of inflammation (n = 3), active perianal disease (n = 3) and patient preference (n = 1) (Figure 1). CONCLUSION: Among patients with CD who undergo UST dose escalation, nearly one fourth are escalated despite achieving remission as defined by HBI <5 without concurrent use of corticosteroids on standard UST dosing. The most common reasons for dose escalation among these patients are early recurrence of symptoms prior to next maintenance dose and evidence of inflammation on endoscopy. UST serum concentrations are uncommonly utilized to guide dose escalation and its utility remains unclear. Larger, prospective studies are needed to determine the long-term benefits and cost effectiveness of dose escalation of UST, as well as to further elucidate effectiveness of dose escalation primarily based on endoscopic findings in the absence of clinical symptoms.Figure 1.: Reasons for Ustekinumab Dose Escalation Among Patients with HBI <5 (n = 38).

S0807 Ustekinumab Dose Intensification in Patients With Crohn’s Disease: Comparing Every 4 and Every 6-Week Dosing

INTRODUCTION: Ustekinumab (UST) therapy for Crohn’s disease (CD) consists of an induction infusion followed by maintenance injections every 8 weeks (q8). However, some pts lose response to this standard dosing. Dose intensification from q8 to q4 has been shown to be safe and effective. However, there is no data comparing outcomes of q4 dosing to q6 dosing. We sought to compare characteristics and clinical outcomes among pts with CD by intensified UST dose interval. METHODS: Retrospective cohort study of adult pts with CD undergoing UST dose intensification at a tertiary referral center between 1/1/2016 and 1/31/2019. Electronic medical records were reviewed for demographics, laboratory data, and CD history. Outcomes assessed within 12 months after dose intensification included corticosteroid-free remission (i.e. Harvey-Bradshaw Index [HBI] < 5 with no use of systemic corticosteroids), change to new biologic therapy, clinical response (i.e. reduction in HBI >3 points for pts with HBI >5), endoscopic improvement, improvement in CT or MRI abdomen, initiation of systemic corticosteroids, IBD surgery, IBD hospitalization, normalization of elevated C-reactive protein (CRP), and normalization of elevated fecal calprotectin. Student’s t-test and Pearson’s chi-squared test were used to compare characteristics and outcomes between q4 and q6 groups. Logistic regression was performed to determine the association between UST dose interval and corticosteroid-free remission. RESULTS: We identified 238 pts who initiated UST for CD. Among these pts, 123 (51.7%) underwent dose intensification to q4 (n = 64), q5 (n = 1), q6 (n = 55), or q7 (n = 3). Characteristics and outcomes by q4 and q6 dosing are presented in Tables 1 and 2, respectively. There were no significant differences in outcomes including remission, change to new biologic, clinical response, imaging or endoscopic improvement, surgery, hospitalization, initiation of corticosteroids, and normalization of CRP or fecal calprotectin. Logistic regression demonstrated no association between UST dose interval and corticosteroid-free remission (q6 vs. q4 OR 1.0, 95% CI 0.4–2.2). CONCLUSION: Dose intensification of UST can be effective to regain response, however there is little guidance on dosing intervals. In this study, q4 dosing was not found to be more effective than q6 dosing. Larger, prospective studies are needed to determine the optimal and most cost-effective dose interval among pts who lose response to standard UST dosing.Table 1Table 2

S3192 Ustekinumab Efficacy in Crohn’s Disease: Results of a Real Life Evaluation in a Specialized Center in Brazil

INTRODUCTION: Ustekinumab is a monoclonal antibody indicated to the treatment of adult patients with active moderate to severe Crohn’s disease. The objective of this study was to evaluate clinical and laboratory responses after two doses of Ustekinumab for Crohn’s disease in patients without previous biologic therapy and also in patients with failure/tolerance to the treatment with biologics (Anti-TNF or Anti-integrin). METHODS: Medical records of 75 patients were analyzed and, among these, 54 were evaluated clinically and in laboratory between weeks 12 and 16 of treatment. RESULTS: Out of the 54 patients assessed, 27/54 (50%) were women, and regarding previous use of biologics: 36/54 (66.7%) presented failure/tolerance to previous biologic therapy [Ustekinumab was the 4th, 3rd, 5th and 2nd biologic used in 12/54 (33.3%); 10/54 (27.8%); 7/54 (19.4%) and 7/54 (19.4%) patients, respectively]. In the presence of previous biological therapy, favorable response to Ustekinumab was observed in 16/36 (44.4%) and in the group where Ustekinumab was the first biologic drug used, the efficacy observed was 13/18 (72.2%). Fecal calprotectin levels were better in responding patients. Four patients of the casuistry have had concomitant psoriasis (two in each group according to the previous use of biologics) and all of them showed improvement of the lesions after the use of Ustekinumab. CONCLUSION: Ustekinumab seems to be a safe and efficacious medication to treat Crohn’s disease in patients that have not been previously exposed to biologic therapy as well as those who had already been exposed to those therapeutic agents. However, better clinical response was observed in patients that used Ustekinumab as first biologic therapy.