Ustekinumab Dose Research Articles

Systematic review with meta-analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases.

Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored. Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity. We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12-31%, 1530 person-years, n=9) per person-year and 25% (95% CI 12-32%, 657 person-years, n=5) per person-year respectively. Clinical response was regained in 58% (95% CI 49-67%, 279 patients, n=8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission. Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.

P458 Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn’s disease (the SPEED-UP study) - A multi-center study from the paediatric IBD Porto group of ESPGHAN

Abstract Background Ustekinumab (UST) is an effective therapy for induction and maintenance of remission in Crohn’s disease (CD). Intensification of UST maintenance dosage has shown effectiveness in some adult patients, but no similar data are available in children. The aim of the study was to evaluate the effectiveness and safety of dose escalation of UST in paediatric CD. Methods This was a retrospective multicenter study from 25 centers affiliated to the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and subsequently underwent dose escalation to intervals shorter than 8 weeks, or re-induction due to active disease. Demographic, clinical, laboratory, endoscopic and imaging data were collected at escalation and during a 12 months follow-up. Clinical remission was defined as weighted Paediatric Crohn’s Disease Activity Index (wPCDAI)<12.5 and clinical response as a decline in >17.5 points. Adverse events were explicitly recorded. Results Sixty-nine children, with a median age of 15.8 (IQR 13.8–16.9) years and disease duration of 4.3 (2.9–6.3) years were included. Sixty-eight (98.6%) and 59 (86.8%) children were biologic and immunomodulators experienced, respectively. UST dose was escalated after a median of 6 (3.6–12) months of therapy. Clinical response and remission were observed in 46 (67%) and 29 (42%) children at 3 months, respectively. The strongest predictor of clinical remission was lower wPCDAI at escalation (p=0.001). The median serum levels of C-reactive protein decreased from 14 (3–28.03) to 5 (1.1–20.5) mg/L at 3 months (p=0.012), and fecal calprotectin from 1110 (499–2300) to 248 (118–1159) mcg/g at 12 months (p=0.05). Endoscopic and transmural healing were achieved in 3/19 (16%) and 2/15 (13%) patients, respectively, of those with available tests. Overall, 13 patients (19%) discontinued therapy due to active disease, at a median of 3 (3–4.5) months. No serious adverse events were reported. Conclusion Two-thirds of children with active CD achieved response following dose escalation of UST.

DOP55 Long-term outcomes after histologic-endoscopic mucosal healing: Results from the UNIFI study in Ulcerative Colitis

Abstract Background In the UNIFI study of ustekinumab (UST) in ulcerative colitis (UC), patients who achieved histo-endoscopic mucosal healing (HEMH; ie, both histologic and endoscopic improvement of mucosa) after induction had higher clinical remission and corticosteroid-free clinical remission rates through 1 year than those who achieved either histologic or endoscopic improvement alone.1 Here, we report the effect of achieving HEMH after induction on long-term symptomatic outcomes through 3 years. Methods Patients who were in clinical response after 8 wks of IV induction with UST 130mg or ~6mg/kg (wk 8 responders) were randomized to maintenance treatment with SC UST 90mg q12w or q8w on entry into maintenance. Those who were not in clinical response to the initial UST dose at wk8 but achieved response at wk16 after receiving a single SC dose of UST 90mg at wk8 (wk16 responders) entered maintenance receiving SC 90mg q8w. After 44 wks of maintenance treatment, patients were given the option to continue in the long-term extension. HEMH was defined as achieving both endoscopic improvement (Mayo endoscopy subscore ≤1) and histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue; based on the Geboes score). Patients with insufficient data for histologic evaluation at the end of induction were excluded. Symptomatic remission was defined as a Mayo stool frequency subscore of 0 or 1 and a Mayo rectal bleeding subscore of 0. Results Of the 438 patients who were wk8 or wk16 responders to UST induction and received UST maintenance, 116 (26.5%) achieved HEMH after induction, 30 (6.8%) achieved endoscopic improvement without histologic improvement (EI), and 106 (24.2%) achieved histologic improvement without endoscopic improvement (HI). Patients who achieved HEMH after induction had higher symptomatic remission and corticosteroid-free symptomatic remission rates at wks92 and 152 than those with EI or HI; the differences were statistically significantly greater at wk152, while they were only numerically greater at wk92 (Table). The differences were primarily driven by patients with HEMH after induction being more likely to maintain symptomatic remission between wks92 and 152, than those with EI or HI alone. Symptomatic remission and corticosteroid-free remission rates decreased between wks92 and 152 in patients with EI or HI only. Conclusion Patients with UC who achieved HEMH after induction with UST were more likely to maintain symptomatic remission and corticosteroid-free symptomatic remission between 2 and 3 years of maintenance treatment than those who achieved EI or HI alone. Reference 1. K Li, et al. Poster 1008. Presented at UEGW 2019. October 22, 2019. Barcelona, Spain.

P579 Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohns’s disease

Abstract Background The efficacy and safety of ustekinumab (UST) intravenous induction followed by 8- and 12- weekly maintenance was established in the UNITI controlled trial. These data report dose intensification for 12- to 8-weekly but not 4-weekly. The effectiveness of this strategy is an important, unanswered real-world question. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly in patients with Crohn’s disease (CD), 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness and safety of this strategy. Methods We performed a retrospective, observational cohort study in a tertiary IBD referral centre. All CD patients treated with UST between 22 January 2015 and 28 October 2020 were identified from a prospective biologic prescription database. Subsequently, data on IBD phenotype, UST interval, drug survival, and corticosteroid-free remission were collected. Dose intensification and drug survival were established with (one minus) Kaplan Meier curves. Logistic regression models were used to identify factors independently associated with dose intensification. Results 163 CD patients (male: 71/163 [43.6%]; median disease duration 9.5 years [IQR 4.8–17.1]) were treated with UST, with median follow-up time of 20.3 months (13.4–38.4). 21/163 patients (12.9%) were biologic naïve, whereas 142 patients (87.1%) were previously treated with one (n=100, 61.3%) or two biologic therapies (n=42, 25.8%). During follow-up, 55/163 patients (33.7%) underwent dose intensification to a 4-weekly (n=50, 30.7%) or 6-weekly (n=5, 3.1%) interval. Median time to dose intensification was 6.1 months (3.9–11.0); after 1 year 29.9% were escalated to 4- or 6-weekly UST. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3–70.9) as well as concomitant steroid use at start of UST (HR 1.8; 1.0–3.1) were independently associated with dose intensification (Figure 1; non-significant: age, CD behaviour, perianal disease activity and UST start dose). Following dose intensification 62.6% patients (29/55) remained on UST beyond 1 year (median time to discontinuation 5.2 months; Figure 2). No licensed treatment options remained in 12/29 patients. At the end of follow-up, (median 8.9 months [4.3–14.8] following dose intensification) 27.8% (15/54) were in corticosteroid-free and clinical remission. Figure 1 Conclusion One third of CD patients treated with UST will undergo dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed two or more biologics were more likely to dose intensify. These are a very refractory group of CD patients, the majority of whom have no licensed treatment options available.

Clinically reversible ustekinumab-induced encephalopathy: case report and review of the literature.

Ustekinumab, a monoclonal antibody against interleukin (IL)-12 and IL-23 approved for the treatment of Crohn’s disease, has shown to be an effective therapy with a favourable safety profile. Clinical trials and real-world studies have reported very few neurological adverse events, including posterior reversible encephalopathy syndrome, idiopathic intracranial hypertension and headache. We describe the case of a 48-year-old man with Crohn’s disease who initiated treatment with ustekinumab on top of ongoing treatment with methotrexate 25 mg/week who presented with an acute-onset encephalopathy that rapidly evolved to severe tetraparesis and akinetic mutism, associated with extensive leukoencephalopathy and restricted diffusion on brain magnetic resonance imaging (MRI), 1 month after the second dose of ustekinumab. Comprehensive in-patient diagnostic testing ruled out vascular, demyelinating, metabolic, tumoral and infectious etiologies. Brain biopsy showed patchy infiltrates of foamy histiocytes with perivascular distribution, associated with edema, diffuse astrocytic gliosis and focal perivascular axonal destruction without demyelination, and ustekinumab-induced neurotoxicity was suspected. After drug discontinuation, the patient presented a complete clinical recovery despite the persistence of leukoencephalopathy. In conclusion, in an era in which biological therapies are continually evolving and expanding, knowledge about the potential neurotoxicity of these new therapies and their management becomes crucial. Although ustekinumab-induced encephalopathy is uncommon, the recognition of this potentially serious side effect is important because prompt withdrawal is associated with a favourable outcome. Whether methotrexate played an additional contributing role is currently unknown, but it is a factor that should be considered.

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis

Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. The primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. ClinicalTrials.gov Identifier: NCT01999868.

S722 Real World Effectiveness of Ustekinumab in Patients With Crohn’s Disease: Findings From a Survey of Gastroenterologists in the U.S.

Introduction: A primary goal of Crohn’s disease (CD) treatment is to induce and maintain long-lasting disease remission. Ustekinumab (UST) is a biologic approved for treating adult moderate-severe CD patients since 2016, but real-world effectiveness data remain limited. To describe clinical characteristics of CD patients currently on UST and investigate their disease status since UST initiation in the real world in the US. Methods: This was a cross sectional study of gastroenterologists and their CD patients in the US (Jan 2020–Mar 2021) using the Adelphi Inflammatory Bowel Disease Specific Programme. Physicians completed patient record forms for their next 5 to 10 consecutively consulting CD patients, recording clinical status, disease duration and location, Harvey Bradshaw Index (HBI) components to derive a patient score, symptoms (from a list of 24), treatment history and current treatment use and dosage. Data were reported for patients receiving UST for >1 day at time of consultation. Comparisons between prevalence of symptoms were made using McNemar’s test. Results: 197 patients on UST were included if they had received ≥1 UST dose. On average, patients had been diagnosed with CD for 4.0 years; mean age was 42.9 years and 58% of patients were male. UST was the first biologic therapy for 50% of the cohort, second biologic for 34% and third biologic for 16%. Mean time on treatment was 11.8 months, with 81% of patients receiving UST for ≥ 3 months and 19% receiving it for < 3 months. Most patients (77%) were receiving UST as a monotherapy at the time of consultation, while 11% were also on corticosteroids, 8% also on immunomodulators, and 5% on both. Amongst patients currently in maintenance, 68% were on UST US labeled dose, 21% were receiving higher and 11% lower than labeled dose. According to HBI, 84% of patients were in remission or had mild disease at last consultation, while 16% of patients had moderate or severe disease (Table 1). The proportion of patients reporting symptoms decreased from treatment initiation to the most recent consultation in patients currently receiving UST (Figure 1). Conclusion: Real-world effectiveness of UST in CD patients was demonstrated, with physicians reporting that most patients were currently in remission or with mild disease and experiencing improvement of symptoms following UST initiation.Figure 1.: Impact of Tofacitinib on Disease Activity Scores.Table 1.: Results of the logistic regression analysis of variables associated with an increased risk of hospitalization among IBD patients and patients with other immune-mediated inflammatory disorders (IMIDs).

S2458 Can SARS-CoV-2 Enterocolitis Trigger New Onset Inflammatory Bowel Disease ?

Introduction: Prevalence of gastrointestinal symptoms in patients infected with SARS-CoV-2 virus is 6.8% - 61.3%. Most common symptoms include diarrhea (8.1% - 33.7%), nausea/vomiting (1.5% - 26.4%), anorexia (12.1% - 26.4%), and abdominal pain (0 – 14.5%). Management involves treating respiratory manifestation of COVID-19, treating co-existing infections, and supportive care. We present a case of severe hemorrhagic enterocolitis managed with a biologic. Case Description/Methods: 47-year-old woman with COVID-19 pneumonia was admitted for extracorporeal membrane oxygenation. She developed copious amounts of watery diarrhea followed by bloody diarrhea. Stool work-up was negative for infectious causes of diarrhea. Colonoscopy revealed diffusely erythematous and friable mucosa with epithelial loss involving the entire colon and distal ileum. She was managed with rectal tube, blood transfusions, parenteral nutrition. Despite escalating doses of numerous anti-diarrheals, topical as well as systemic steroids, copious volumes of bloody diarrhea continued. Repeat colonoscopic biopsies demonstrated CMV-like inclusions with borderline elevated serologic titers. Despite successful eradication of CMV with prolonged courses of ganciclovir and foscarnet, hemorrhagic diarrhea continued. Several upper and lower endoscopies suggested worsening mucosal erythema and friability, predominantly involving small bowel and colon. Given COVID enterocolitis refractory to all the above treatments, induction therapy with a biologic was considered to treat possible de novo inflammatory bowel disease (IBD) versus immune mediated effects of COVID-19 enterocolitis. After induction doses of Ustekinumab, an IL-12 and IL-23 inhibitor, volume of diarrhea reduced and bloody diarrhea resolved, facilitating removal of rectal tube, resumption of oral nutrition, discontinuation of anti-diarrheals. Patient was discharged on maintenance Ustekinumab. Follow-up endoscopic evaluation demonstrated mucosal healing, with epithelial regeneration and chronic inflammatory changes of crypt distortion. Discussion: SARS-CoV-2 infection triggered an inflammatory cascade in the intestinal tract leading to altered or increased immune response, probably on a background of genetic predisposition, in our patient. Initiation of Ustekinumab, IL-23/IL-12 inhibitor, likely resulted in suppression of the severe systemic inflammatory response, resulting in clinical, endoscopic and pathological response.Figure 1.: (a) demonstrates endoscopic appearance of transverse colon with erythema, friability and hemorrhages prior to treatment with biologic (b) demonstrates epithelial denudation with minimal acute inflammation in colonic mucosa prior to treatment with biologic (c) demonstrates endoscopic appearance of transverse colon with resolving erythema after treatment with biologic (d) demonstrates chronic inflammatory changes with crypt architectural distortion and pyloric gland metaplasia after induction of remission with biologic, many months after initial presentation.

Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease.

Some patients with Crohn's disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure-response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks. Out of 135 consecutive patients, 44 with active Crohn's disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn's disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations. Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551-0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545-0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization. Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.

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.

Re-induction with intravenous Ustekinumab after secondary loss of response is a valid optimization strategy in Crohn's disease.

Re-induction with intravenous ustekinumab after secondary loss of response in Crohn's disease is a relatively new strategy to regain efficacy. This real-world cohort study aimed to evaluate its effectiveness and safety. Crohn's disease patients with loss of response after initial response to ustekinumab and treated with a second intravenous dose of ustekinumab were included. Clinical, biochemical and endoscopic data were collected. Primary outcome was drug survival. Secondary effectiveness outcomes included clinical remission, primary nonresponse and adverse events. In total, 31 Crohn's disease patients were included after re-induction with intravenous ustekinumab. All patients had failed prior biologic therapy, that is 77% were exposed to two or more antitumor necrosis factor agents and 65% were exposed to vedolizumab prior to initiation of ustekinumab treatment. Median treatment duration between initial treatment and re-induction with intravenous ustekinumab was 11.1 months (interquartile range 6.9-19.5). Ustekinumab therapy after a second dose of intravenous ustekinumab was maintained in 74 and 71% of the patients at weeks 20 and 52. Clinical remission rates after re-induction at weeks 8, 20 and 52 were 37, 56 and 45%, respectively. Nonresponse occurred in 16% of the patients. Adverse events were reported in four patients. Re-induction with intravenous ustekinumab after secondary loss of response results in continuation of ustekinumab treatment for at least 1 year in almost three-quarters of patients and in clinical remission in half of patients after 1 year. Therefore, ustekinumab re-induction may be considered an important rescue treatment option in patients with refractory Crohn's disease.

Population pharmacokinetic-pharmacodynamic model-based exploration of alternative ustekinumab dosage regimens for patients with Crohn's disease.

In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (~6mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes. Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 μg/g to 694 μg/g (EC50 ). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 μg/g to 214 μg/g (EC50 ). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing. The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.

61-Year-Old Man With Shortness of Breath and Cough

A 61-year-old man presented with 3 weeks of shortness of breath and cough productive of occasional brown sputum. His medical comorbidities included Crohn colitis, deep vein thrombosis and pulmonary embolism on chronic anticoagulation, obstructive sleep apnea, obesity, impaired fasting glucose, depression, and latent tuberculosis status post 9 months of isoniazid. For the past year, his Crohn disease treatment regimen included methotrexate, and he received his first dose of ustekinumab 6 weeks before presentation.

Long-term efficacy and safety of ustekinumab for moderate-to-severe psoriasis: A 9-year real-life experience from a tertiary referral center in Turkey.

There is a paucity of data on long-term (≥5-year) outcomes of ustekinumab therapy for psoriasis in real-life clinical practice. This observational, retrospective study aimed to evaluate the long-term efficacy and safety profile of ustekinumab in 52 adult patients with moderate-to-severe chronic plaque psoriasis who were treated with ustekinumab for at least 28 weeks and a maximum of 105 months in our tertiary referral center in Turkey, between 2010 and 2019. Response to therapy was assessed using Psoriasis Area and Severity Index (PASI). Logistic regression analysis was performed to determine significant associations (p-value <0.05) with response to treatment. The PASI50, PASI75, PASI90, and PASI100 response rates were 97.8%, 88.9%, 53.3%, and 35.5%, respectively, at year 1 and 100%, 80.0%, 60.0%, and 40.0%, respectively, at year 5. Non-obesity was independently associated with PASI90 response at year 2 (p=0.043), while biologic-naivety was independently associated with PASI90 responses at year 2 (p=0.047) and year 3 (p=0.021). An absolute PASI score of ≤3 was achieved by 82.2% and 80.0% of the patients at year 1 and year 5, respectively. Nine patients received adjuvant therapy and nine underwent ustekinumab dose escalation. These strategies were effective for recapturing clinical response in most patients. Ustekinumab was generally well-tolerated with no dose-related and cumulative toxicity, or drug interaction over a mean of 33.5 ± 21.1months. The main reasons for discontinuation were secondary failure and loss to follow-up. Our 9-year real-life clinical experience demonstrates that ustekinumab is an efficacious and safe treatment option for long-term therapy of moderate-to-severe plaque psoriasis.

P478 Effectiveness of ustekinumab dose escalation in Crohn’s disease patients with insufficient response to standard-dose subcutaneous maintenance therapy: an observational multicentre study

Abstract Background Ustekinumab is a human monoclonal antibody that targets interleukin (IL)-12 and IL-23 and it is effective for the treatment of Crohn’s disease (CD). However, a group of patients will not respond or over time will experience loss of response (LOR) to ustekinumab. Evidence supporting the effectiveness of ustekinumab dose escalation for LOR is scarce. The aim of this study was to assess the effectiveness of ustekinumab dose escalation in a cohort of patients with active CD Methods Multicentric retrospective cohort study conducted in 5 tertiary Andalusian centers. Patients with active CD who received a standard-dose intravenous (IV) induction and at least one subcutaneous (SC) ustekinumab dose were included. All enrolled patients received dose escalation by either shortening the interval between the maintenance doses to every 4 or 6 weeks, IV reinduction or a combination of strategies. The primary outcome of the study was to assess corticosteroid (CS)-free clinical remission (HBI ≤4) at week 16. Secondary outcomes were CS-free clinical response (decrease of HBI ≥ 3 points from baseline) at week 16 and on the last follow-up, CS-free clinical remission on the last follow-up and ustekinumab persistence after dose escalation Results A total of 84 patients were included (54,8% female, median duration of CD 13,5 years). A 47,5% of the patients had history of previous abdominal surgery and 55% had been treated with 2 or more biologics. Patients were dose-escalated after a median treatment duration of 37 weeks (IQR 23–54). The most frequent type of dose escalation was the 90 mg every 4 weeks regimen (58%). A 25% of the patients were on concomitant immunomodulators at escalation. At week 16 from dose escalation the proportion of patients in CS-free response was 50/84 (59%) including 18/84 (21,4%) in CS-free remission. Follow-up data beyond week 20 were available for 61/84 patients (72.6%). On the last follow-up visit, 29/61 (47,5%) patients responded to treatment without concomitant CS of which 19/61 (31%) were in CS-free clinical remission. Systemic CS were discontinued in 21/44 (47.7%) patients who were on CS at the time of dose escalation. Ustekinumab was discontinued in 14/84 (17%) of the patients due to clinical non-response (ustekinumab persistence was 81% at 14 months of follow-up). Adverse events following dose escalation were reported in 4 of the 84 patients (7.7%), none of them were serious. Conclusion Dose escalation of ustekinumab maintenance was effective in over 50% of the patients and the treatment persistence was high. This strategy should be considered in patients who are not responsive or have LOR to ustekinumab on an 8-week dose maintenance interval

P476 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.AimsPrimary: to evaluate the durability of ustekinumab treatment in UC patients in clinical practice. Secondary: to assess the short-term response (at week 16) and the long-term effectiveness (at maximum follow-up) and to assess the safety of ustekinumab in clinical practice.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.Results95 patients were included (table 1). At week 16, 53% of patients had clinical response (including 35% of patients in remission) (figure 1). In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with clinical remission. Long-term remission is represented in figure 2. 36% 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 (figure 3); 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. ConclusionUstekinumab 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.

P509 Influence of concomitant immunosuppresives in retention rate in Crohn′s Disease patients under ustekinumab in the SUSTAIN Study

Abstract Background Whether to use biologic treatment for inflammatory bowel disease as monotherapy or in combination with immunosuppressives has been a matter of debate in the last years. We aimed to evaluate if immunosuppressants influenced the retention rate of ustekinumab in Sustain, the largest study evaluating its use in clinical practice, having the longest follow-up period reported to date. Methods Retrospective, multicentre study (&amp;gt;60 sites) including patients with active Crohn′s Disease (CD) [(Harvey-Bradshaw (HBI)&amp;gt;4)] who received ≥1 dose of ustekinumab intravenously before July 2018. Data on concomitant immunomodulatory therapy (if any) with azathioprine, mercaptopurine, methotrexate or others at the start of ustekinumab treatment and during follow-up were documented. Clinical remission was defined as HBI≤4 and response as ≥3 points decrease from baseline. Loss of response (LoR) was defined as reappearance of symptoms that led to intensifying the treatment dose, adding another medication to control CD, switching or surgery in patients with short-term remission. The retention rate in patients on ustekinumab receiving or not immunosuppressive treatment was evaluated by descriptive analysis and Kaplan-Meier survival curves. Predictive factors were assessed by Cox-regression. Data quality was assured by remote monitoring. Results 463 CD patients were included. Prior CD treatments to ustekinumab were collected: the majority of patients received steroids, immunosuppressants and biologics. Figure 1 shows the percentage of patients on treatment with each type of drug and whether or not they continued to receive it when they started ustekinumab, in the case of steroids and immunosuppressants. Reasons for discontinuation of previous immunosuppressive treatments for CD were as follows: failure (37.5%), sustained remission (5.8%), adverse event (47.6%), medical decision (4%), other reasons (5.1%). During ustekinumab treatment, 163 patients (35.2%) received immunosuppressants (listed in figure 2). Sixty-six (14.3%) patients had their immunosuppressant withdrawn during treatment. Retention was observed in 77.9% of patients with concomitant immunosuppressive therapy versus 76.3% of patients without. There weren′t statistically significant differences between the two populations (p=0.712). Figure 3. The patient-year discontinuation rate for patients who didn′t receive concomitant immunosuppressants was 17.5 versus 18.9 in those who received them. Conclusion No effectiveness differences were seen by adding immunosuppressants to ustekinumab, reinforcing the low immunogenic profile of this drug and reducing the risk of additional side effects and toxicity.

P263 Influence of Crohn′s Disease phenotype in the retention rate of ustekinumab treatment: SUSTAIN Study

Abstract Background Crohn′s disease (CD) is a progressive inflammatory bowel disease that can lead to complications such as strictures or penetrating disease, and ultimately surgery, representing a complex clinical challenge in the care of patients. We aimed to evaluate the influence of CD phenotype in the retention rate of ustekinumab in the Sustain study. Methods Retrospective, multicentre study (&amp;gt;60 sites) including patients with active CD [(Harvey-Bradshaw (HBI)&amp;gt;4)] who received ≥1 dose of ustekinumab intravenously before July 2018. Clinical remission was defined as HBI≤4 and response as ≥3 points decrease from baseline. Loss of response (LoR) was defined as reappearance of symptoms that led to intensifying the treatment dose, adding another medication to control CD, switching or surgery in patients with short-term remission. Disease characteristics were collected (date of diagnosis; location; behaviour: inflammatory, stenosing or penetrating; presence of perianal disease or extraintestinal manifestations; previous surgeries, etc.). The retention rates in patients on ustekinumab depending of their disease phenotype were evaluated by descriptive analysis and Kaplan-Meier survival curves. Survival curves were compared using the log-rank test. Predictive factors were assessed by Cox-regression. Data quality was assured by remote monitoring. Results 463 CD patients were included (Table 1). 87 patients (18.6%) had penetrating CD in our cohort. The probability of maintaining UST treatment was 91% at 6, 83% at 12, 76% at 18 and 73% at 24 months. Similar retention rates were observed in patients with inflammatory (77.6%), stricturing (76.4%) and penetrating (79%) disease behaviour (p&amp;gt;0.05). Figure 1. Conclusion Ustekinumab has shown to be equally effective in the treatment of inflammatory, stricturing and penetrating CD phenotype in Sustain, the largest study evaluating its use in CD in clinical practice, having the longest follow-up period reported to date.

OP35 Effect of maintenance ustekinumab on corticosteroid-free endoscopic and clinical outcomes in patients with Crohn’s Disease - Week 48 analysis of the STARDUST trial

Abstract Background The STARDUST study demonstrated that ustekinumab (UST), using either a treat-to-target (T2T) or standard of care (SoC) strategy, may induce and maintain endoscopic and clinical response and remission in Crohn’s disease (CD). Primary endpoint, safety, and efficacy have been reported previously.1 Because corticosteroid (CS) sparing is an important aim of CD management, we compared the efficacy of UST T2T vs SoC in achieving CS-free clinical remission and endoscopic response. Methods Adult patients (pts) with moderate–severely active CD who were CDAI 70 responders after 16 weeks (W) of induction, comprising a single dose of UST 6 mg/kg iv followed by UST 90 mg SC at W8, were randomized to either T2T or SoC arms. In the T2T arm, choice of UST maintenance dosage (q12w or q8w) was based on endoscopic improvement at W16, followed by clinical and biomarker-directed dose escalation up to q4w; in the SoC arm, UST q12w or q8w dosage was based on EU SmPC. Primary endpoint was endoscopic response (Simple Endoscopic Score in CD [SES-CD] decrease from baseline [BL] ≥50%) at W48. For pts on CS at W16, CS tapering was mandatory. At W48, CS-free clinical remission (CDAI &amp;lt;150 and no CS for ≥30 days) and CS-free endoscopic response (reduction from BL in SES-CD ≥50% and no CS for ≥30 days) were evaluated. Results Of 500 pts enrolled, 441 achieved a CDAI 70 response at W16 and were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3%, respectively, completed W48. Among clinical remitters and responders at W16 (start of CS tapering), in both T2T and SoC arms more than 70% were still in remission or response at W48 (Figure 1). CS use throughout 48 weeks of treatment is summarized in Table 1. At W48, in T2T and SoC arms similar rates were noted for CS-free endoscopic response (33.6% and 28.5%, respectively) and CS-free clinical remission (56.4% and 63.3%, respectively). Notably, in T2T and SoC arms the CS-free clinical remission rate among pts on CS at BL was 44.1% and 45.1%, respectively (Figure 2). Among W48 endoscopic responders (T2T, n=83; SoC, n=66), CS-free endoscopic response rate was 89.2% and 95.5%, respectively; among W48 clinical remitters (T2T, n=135; SoC, n=154), CS-free clinical remission rate was 91.9% and 90.9%, in T2T and SoC arms, respectively. Conclusion Pts treated with UST under T2T or SoC strategies achieved similar rates of CS-free clinical remission and endoscopic response over 48 weeks. Overall for pts on CS at BL, UST reduced the need for CS while achieving response/remission. Most (&amp;gt;89%) pts with endoscopic response/clinical remission at W48 were also CS-free responders/remitters. Reference

P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease

Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.