Efficacy Of Ustekinumab In Patients Research Articles

Machine learning using clinical data at baseline predicts the medium-term efficacy of ustekinumab in patients with ulcerative colitis

Predicting the therapeutic response to biologics before administration is a key clinical challenge in ulcerative colitis (UC). We previously reported a model for predicting the efficacy of vedolizumab (VDZ) for UC using a machine-learning approach. Ustekinumab (UST) is now available for treating UC, but no model for predicting its efficacy has been developed. When applied to patients with UC treated with UST, our VDZ prediction model showed positive predictive value (PPV) of 56.3% and negative predictive value (NPV) of 62.5%. Given this limited predictive ability, we aimed to develop a UST-specific prediction model with clinical features at baseline including background factors, clinical and endoscopic activity, and blood test results, as we did for the VDZ prediction model. The top 10 features (Alb, monocytes, height, MCV, TP, Lichtiger index, white blood cell count, MCHC, partial Mayo score, and CRP) associated with steroid-free clinical remission at 6 months after starting UST were selected using random forest. The predictive ability of a model using these predictors was evaluated by fivefold cross-validation. Validation of the prediction model with an external cohort showed PPV of 68.8% and NPV of 71.4%. Our study suggested the importance of establishing a drug-specific prediction model.

OP37 Effect of the HLA-DQA1*05 allele on the efficacy of ustekinumab in patients with Crohn's Disease. Multicenter study based on the ENEIDA registry of GETECCU

Abstract Background HLA-DQA1*05 carriage is associated with the development of anti-drug antibodies and loss of response (LOR) to tumour necrosis factor antagonists (anti-TNF) in patients with inflammatory bowel diseases (IBD)1. Ustekinumab has shown very low rates of immunogenicity and presumably will not be affected by this risk. Identifying patients at high risk of treatment failure would be important when selecting therapy for IBD. The objective of this analysis was to investigate the relationship between the HLA- QA1*05 allele and ustekinumab on development of LOR and drug persistency. Methods This is a retrospective cohort study from a prospectively maintained ENEIDA registry. LOR was defined as recurrence or worsening of IBD related symptoms that required a change or intensification in treatment, hospitalization or surgery. Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. The HLA-DQA1*05 allele was determined from a saliva sample (kit OGD-600 de DNA Genotek Oragene) and DNA extraction with the Maxwell® RSC-Stabilized Saliva DNA kits. Results 204 patients with Crohn's disease were included. Previous exposure to biological drugs was 96% (61% ≥2 biological drugs). Basal faecal calprotectin levels were 907±970μg/g and PCR levels 16.2±25 mg/dL. The median follow-up was 417±154 days. During this period, 25%, 16% and 13% of the patients required drug intensification, hospitalization or surgery, respectively. 43% of the patients included were carriers of one or two copies of the HLA-DQA1*05 allele. The presence/absence of this allele was not associated with LOR to ustekinumab (20% vs 16%, p = ns) nor with drug withdrawal (11% vs 6%, p = ns). In the multivariate analysis (COX regression), only the number of previous biological drugs was associated with ustekinumab persistency. Conclusion The presence of the HLA-DQA1*05 allele is not related to LOR or persistency of ustekinumab treatment. First-line treatment with ustekinumab rather than anti-TNF agents may be considered in HLA-DQA1*05-positive patients, particularly when the use of a concomitant immunosuppressant is contraindicated. 1. Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea CM, et al. PANTS Consortium. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology. 2020 Jan;158(1):189-199.

Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1year and 58.9% at 2years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Predictive factors of the clinical efficacy of ustekinumab in patients with refractory Crohn's disease: tertiary centers experience in Japan.

Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn's disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn's Disease Activity Index < 150 and CRP < 0.3mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2years) and higher baseline serum albumin levels (≥ 3.1g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels.

P389 Efficacy and safety of ustekinumab in patients with Crohn’s disease refractory to anti-tumour necrosis factor: real clinical practice

Abstract Background The efficacy of ustekinumab in patients with Crohn’s disease (CD) refractory to anti-TNF is worse than in anti-TNF naïve patients. Methods Retrospective study of patients with CD refractory or intolerant to TNF initiating ustekinumab between January 2013 and March 2020, with a minimum follow-up of 12 months, and without corticosteroid treatment. Our aim was evaluated clinical response (reduction of CDAI &amp;gt;100), clinical remission (CDAI &amp;lt;150) and biochemical remission (CDAI &amp;lt;100 and CRP &amp;lt;1 mg/L and faecal calprotectin &amp;lt;100 µg/g) in short and long term. Results A total of 49 patients with a medium follow-up of 28 months (IQR:13-37) were included. Patients baseline characteristics are reflected in Table 1. In 20% patients the induction was made subcutaneous (90 mg/week for 4 weeks). At week 52, clinical response, clinical remission and biochemical remission was 93%, 82% and 54% respectively (Figure 1). In the long term (3 years), 62% had clinical response, 52% remained in clinical remission, and 48% showed biochemical remission. 1/3 of patients needed intensification every year. Ustekinumab treatment discontinuation was observed in 13 patients (27%) mainly due to lack of response (6[12%]: primary, 7[14%]: secondary). No serious adverse effects have been reported. Conclusion About 50% of the patients are in clinical and biochemical remission at week 152 in a real-life cohort of anti-TNF-exposed CD patients. With a harder remission definition including biochemical parameters, our results in real life are similar to pivotal studies at week 152. Nevertheless, at week 52 our remission rates were higher.

Ustekinumab for Ulcerative Colitis

Ustekinumab for Ulcerative Colitis

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).

P087 REAL-WORLD EFFECTIVENESS OF USTEKINUMAB IN ULCERATIVE COLITIS

Abstract Introduction Ulcerative colitis (UC) is a chronic inflammatory condition of the colon. Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 FDA approved for use in Crohn’s disease. A recent randomized control trial UNIFI [Sands et al, NEJM 2019] demonstrated the efficacy of ustekinumab in patients with moderate-to-severe UC. The goal of this study was to describe the real-world effectiveness of ustekinumab in patients with UC. Methods A retrospective, single-center, chart review was performed of all patients with UC who received ustekinumab between January 2017 and October 2019. As ustekinumab is not yet FDA approved for UC, for patients who have exhausted other treatment options its use is considered “off-label”. Patient demographics, disease characteristics and prior treatment history were recorded. The primary outcome was clinical remission at 12 months after initiation of ustekinumab. Secondary outcomes were clinical response and remission at 3 months, and endoscopic response, corticosteroid-free remission, and deep remission (combined clinical and endoscopic remission) at 12 months (all outcomes defined in Figure 1). Results 19 pts received ustekinumab for moderate-to-severe UC. They were 47.4% male with a mean age of 42.7 ±17.0 years. Mean total Mayo score was 7.6 ± 1.5 and 47.4% of pts had disease limited to the left colon. 18/19 pts received a weight-based IV induction dose (520 mg, 390 mg or 260 mg for &amp;gt; 85 kg, &amp;gt;55 to 85 kg or ≤55 kg respectively) and 1/19 received 90mg subcutaneous injection as induction. All pts received 90mg subcutaneous injections every 8 weeks initially for maintenance, and 9/19 eventually needed dose escalation to every 4 weeks. All pts had prior exposure to a TNF antagonist, 26.3% had exposure to two or more TNF antagonists, 89.5% had prior failure of vedolizumab and 10.5% had prior failure of tofacitinib (Table 1). At 12 months, 38.5% had a clinical response, 30.8% were in clinical remission, 38.5% had an endoscopic response, and 30.8% were in deep remission (Figure 1). Two infectious adverse events (shigellosis, Escherichia coli enterocolitis) were reported in follow-up. Conclusions Ustekinumab is effective in patients with UC. The efficacy of ustekinumab in the UNIFI trial translated to our real-world population, despite higher rates of prior biologic failure with TNF antagonists and vedolizumab in our cohort. Further studies of large, real-world cohorts are needed to assess the long-term effectiveness and safety of ustekinumab in UC.

Efficiency ustekinumab in the treatment of patients with psoriasis with metabolic disorders

One of the goals of psoriasis therapy is to achieve sustainable remission. Currently, genetically engineered biological drugs are most effective in the treatment of psoriasis. However, there is a certain proportion of patients with insufficient efficiency of genetic engineering biological therapy. One of the reasons for reducing the therapeutic response in patients with psoriasis may be the presence of metabolic syndrome. Objective: to study the therapeutic efficacy of ustekinumab in patients with psoriasis with metabolic syndrome. Materials and methods: 52 patients with plaque psoriasis receiving ustekinumab therapy were observed: 25/52 (48.0%) patients with metabolic syndrome, 27/52 (52.0%) - without metabolic syndrome. The proportion of patients who reached PASI75 by the 12th week among patients with psoriasis with and without metabolic syndrome was 17/25 (68.0%) and 23/27 (85.2%) (p&gt;0.05), respectively; 24th week - 15/25 (60.0%) and 25/27 (92.6%) (p&lt;0.05), respectively; 48th week-14/25 (56.0%) and 24/27 (88.9%) (p&lt;0.05). Conclusion: therapeutic efficacy of ustekinumab is higher in patients with psoriasis without metabolic syndrome than in patients with metabolic syndrome.

P460 Efficacy of ustekinumab in patients with anti-TNF refractory Crohn’s disease: data from a real-world study in Brazil

P460 Efficacy of ustekinumab in patients with anti-TNF refractory Crohn’s disease: data from a real-world study in Brazil

Ustekinumab Is Effective for the Treatment of Crohn's Disease of the Pouch in a Multicenter Cohort.

Crohn's disease (CD) of the pouch and chronic pouchitis occur in approximately 10% of patients after ileal pouch-anal anastomosis (IPAA) for refractory ulcerative colitis (UC) or UC-related dysplasia. The efficacy of anti-tumor necrosis factor (anti-TNF) agents and vedolizumab have been reported for the treatment of CD of the pouch and chronic pouchitis, but little is known regarding the use of ustekinumab in these settings. Our primary aim was to evaluate the efficacy of ustekinumab for these conditions. This is a retrospective, multicenter cohort study evaluating the efficacy of ustekinumab in patients with CD of the pouch and chronic pouchitis. Clinical response or remission was judged by the treating physician's assessment at 6 months. Fifty-six patients (47 with CD of the pouch and 9 with chronic pouchitis) were included the study. Of these, 73% had previously been treated with either anti-TNF therapy, vedolizumab, or both after IPAA. Among patients with CD of the pouch and chronic pouchitis, 83% demonstrated clinical response 6 months after induction with ustekinumab. Responders demonstrated significantly less pouch inflammation on endoscopy when compared with nonresponders (29% vs 100%; P = 0.023). Higher mean body mass index at induction (26.3 vs 23.7; P = 0.033) and male sex (83% vs 30%; P = 0.014) were significant predictors of nonresponse to ustekinumab in those with CD of the pouch. In this refractory patient population, ustekinumab appears to be a safe and effective treatment for chronic pouchitis and CD of the pouch in biologic-naïve patients and those with prior anti-TNF or vedolizumab therapy failure. 10.1093/ibd/izx005_video1 izy302.video1 5844889626001.

Mo1875 - Efficacy of Ustekinumab in Patients with Refractory Perianal Crohn's Disease in a Tertiary Care IBD Center

Mo1875 - Efficacy of Ustekinumab in Patients with Refractory Perianal Crohn's Disease in a Tertiary Care IBD Center

AB0751 Efficacy of Ustekinumab in Patients with Active Psoriatic Arthritis: 1 Year Results

BackgroundPsoriatic arthritis (PsA) is characterised by arthritis, psoriasis, sacroilitis, enthesitis and dactylitis. The efficacy of tumor necrosis factor-α (TNF-α) inhibitor has been demonstrated in different controlled clinical trials and observational...

Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial

Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis. In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3·0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice-web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. This trial is registered with ClinicalTrials.gov (NCT01009086) and EudraCT (2009-012264-14). Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned-206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42·4%] in the 45 mg group and 101 of 204 [49·5%] in the 90 mg group) than placebo-treated (47 of 206 [22·8%]) patients achieved ACR20 at week 24 (p<0·0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41·8%] vs 86 of 205 [42·0%]). Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments. Janssen Research & Development.

Long‐term efficacy of ustekinumab in patients with moderate‐to‐severe psoriasis treated for up to 5 years in the PHOENIX 1 study

Ongoing evaluation of biological agents in patients with moderate-to-severe psoriasis is needed to support their long-term use. To evaluate long-term efficacy and safety of ustekinumab through 5 years in the PHOENIX 1 study. Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every-12-weeks thereafter; placebo patients crossed-over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥ 1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders [Weeks 28/40] re-randomized at Week 40 to continue every-12-week maintenance) and Partial Responders (i.e. <PASI 75 responders adjusted to every-8-week maintenance at Weeks 28 or 40). Safety endpoints were evaluated through Week 264 for the Overall Population. Overall, 68.7% (517/753) of ustekinumab-treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders [79.1% (45 mg) and 80.8% (90 mg)] and Partial Responders [57.6% (45 mg) and 55.1% (90 mg)]. With 3104 patient-years of follow-up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses. Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.

Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years

An unmet need remains for safe and effective long-term treatments of psoriasis. To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial. Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50-74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician's Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures. Overall, 79·8% of the ustekinumab-treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. CONCLUSIONS; Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.