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Mitchel EB, Dolinger MT, Constant B, Wang Z, Guisado D, Gao M, Fusillo S, Baldassano RN, Kelsen J, Dubinsky M, Huang J, Albenberg L. Ustekinumab is safe and effective in pediatric patients with Crohn's disease. J Pediatr Gastroenterol Nutr 2025; 80:653-663. [PMID: 39888083 DOI: 10.1002/jpn3.12452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 09/11/2024] [Accepted: 09/21/2024] [Indexed: 02/01/2025]
Abstract
OBJECTIVES Real-world data on ustekinumab for the treatment of pediatric Crohn's disease (CD) are limited. This study sought to evaluate the effectiveness, long-term durability, and safety of ustekinumab in the treatment of children with CD. METHODS A retrospective longitudinal cohort study of children with CD treated with ustekinumab from two large centers between 2015 and 2020 was performed. The primary outcome was frequency of steroid-free clinical remission at 1 year. Secondary outcomes included time to steroid-free clinical remission, frequency of clinical and biochemical remission, drug escalation and discontinuation, serum level data, and adverse events. Standard descriptive and comparative statistics were performed. Logistic regression was used to identify factors associated with steroid-free remission at 1 year. Kaplan-Meier curves were used to visualize time-to-event relationships for outcomes. RESULTS A total of 101 patients were included. Median follow-up time on ustekinumab was 16.6 months (interquartile range [IQR]: 8.71-31.2) with drug failure in 28% at 1 year. Fifty-nine patients were in steroid-free clinical remission at 1 year. Higher baseline disease activity (odds ratio [OR]: 0.91 (95% confidence interval [CI]: 0.84-0.97), p = 0.01) and stricturing/penetrating disease phenotype (OR: 0.14 (95% CI: 0.03-0.65), p = 0.02) were associated with decreased likelihood of steroid-free clinical remission at 1-year. Ustekinumab drug escalation occurred in 70% of patients, and after escalation, 50 (70%) achieved clinical remission, and 49 (69%) achieved steroid-free remission at the last follow-up. Adverse events were rare and did not require therapy discontinuation. CONCLUSIONS Ustekinumab is effective and safe in the treatment of children with CD. Escalation of therapy occurs frequently but results in sustained durability.
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Affiliation(s)
- Elana B Mitchel
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Michael T Dolinger
- Susan and Leonard Feinstein Inflammatory Bowel Disease Center at Mount Sinai, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Brad Constant
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Zi Wang
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Daniela Guisado
- Susan and Leonard Feinstein Inflammatory Bowel Disease Center at Mount Sinai, New York, New York, USA
| | - Michael Gao
- Susan and Leonard Feinstein Inflammatory Bowel Disease Center at Mount Sinai, New York, New York, USA
| | - Steven Fusillo
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Robert N Baldassano
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Judith Kelsen
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Marla Dubinsky
- Susan and Leonard Feinstein Inflammatory Bowel Disease Center at Mount Sinai, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jing Huang
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Lindsey Albenberg
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Petrov JC, Al-Bawardy B, Alzahrani R, Mohamed G, Fine S. Rates, Predictors, and Outcomes of Ustekinumab Dose Escalation in Inflammatory Bowel Disease. J Clin Gastroenterol 2025; 59:232-236. [PMID: 38595134 DOI: 10.1097/mcg.0000000000002003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 03/04/2024] [Indexed: 04/11/2024]
Abstract
OBJECTIVE Ustekinumab (UST) is effective for the induction and maintenance of remission in inflammatory bowel disease (IBD). However, a significant proportion of patients will require UST dose escalation. We sought to determine the rates, predictors, and outcomes of UST dose escalation in patients with IBD. PATIENTS AND METHODS This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. Primary outcomes were the rates and predictors of UST dose escalation. Secondary outcomes included steroid-free clinical remission, endoscopic healing, and normalization of serum c-reactive protein in patients who underwent UST dose escalation. RESULTS A total of 198 patients were included (58% females and 76.7% with Crohn's disease). UST dose was escalated by 55.5% (n = 110). Mean baseline albumin was lower in the UST dose escalation group at 3.86 ± 0.47 versus 4.03 ± 0.45 g/dL ( P = 0.044). The mean hemoglobin was lower in the UST dose escalation group at 12.1 ± 1.83 versus 12.7 ± 1.42 ( P = 0.049). On multivariate analysis, male sex alone was associated with the need for dose escalation (odds ratio: 4.08, 95% CI: 1.20 - 13.90; P = 0.025). In the UST dose escalation group, 66.1% achieved steroid-free clinical remission, 55.8% had normalization of c-reactive protein, and 35.8% achieved endoscopic healing. CONCLUSIONS UST dose escalation was needed in more than half of patients with IBD in this real-world cohort. UST dose escalation resulted in clinical remission in more than half of the cohort and endoscopic healing in one-third of patients.
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Affiliation(s)
| | - Badr Al-Bawardy
- Department of Internal Medicine, Section of Digestive Diseases
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, King Faisal Specialist Hospital and Research Center
- College of Medicine, Alfaisal University
| | - Raneem Alzahrani
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
| | - Gamal Mohamed
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
| | - Sean Fine
- Division of Gastroenterology, Warren Alpert Medical School, Brown University, Providence, RI
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Alhadab A, Almarhoon A, AlAlwan A, Hammo A. Clinical effectiveness and safety of ustekinumab in youth with refractory inflammatory bowel disease: A retrospective cohort study. Saudi J Gastroenterol 2025; 31:59-67. [PMID: 38597337 DOI: 10.4103/sjg.sjg_7_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/18/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) incidence and prevalence has been increasing worldwide. Limited data exists on the effectiveness of ustekinumab (UST) in children. We aimed to describe the effectiveness and safety of UST in pediatric patients with IBD. METHODS A single-center retrospective study was conducted between January 2017 and February 2022. The study included patients ≤16 years of age who were treated with UST and followed up for ≥1 year. Clinical remission was defined as a score of the Pediatric Crohn's Disease (CD) and Pediatric Ulcerative Colitis (UC) Activity Indices ≤10 at week 52. RESULTS Thirteen patients who had failed anti-tumor necrosis factor-α (anti-TNFα) therapy were included, eight (61.5%) with CD and five (38.5%) with UC. The median age was 13 years (interquartile range [IQR]: 11.5 to 14). UST treatment was initiated at a median age of 3 years (IQR: 2.3 to 7) after diagnosis. Ten patients (76.9%) achieved clinical remission. There were no statistically significant differences in characteristics between patients who achieved and did not achieve clinical remission. Biochemical remission (BioR) was achieved in six patients (46.2%). Body mass index (BMI) significantly improved, C-reactive protein (CRP) significantly decreased, and the need for corticosteroids significantly decreased in the remission group. Endoscopy conducted post-treatment in seven patients confirmed remission in six patients. Adverse events included two cases of infection and one of headache. CONCLUSIONS UST was effective as a secondary biologic therapy for the induction and maintenance of remission in patients with anti-TNFα refractory IBD. At one year, 84% of patients remained on UST with no severe adverse reactions reported.
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Affiliation(s)
- Abdulhamid Alhadab
- Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, McMaster University, Hamilton, Canada
- Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Amal Almarhoon
- Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Amena AlAlwan
- Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - AbdelHai Hammo
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Arkansas for Medical Sciences, USA
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Fanizzi F, Allocca M, Fiorino G, Zilli A, Furfaro F, Parigi TL, Peyrin-Biroulet L, Danese S, D’Amico F. Raising the bar in ulcerative colitis management. Therap Adv Gastroenterol 2024; 17:17562848241273066. [PMID: 39600566 PMCID: PMC11589388 DOI: 10.1177/17562848241273066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/17/2024] [Indexed: 11/29/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC.
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Affiliation(s)
- Fabrizio Fanizzi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Gionata Fiorino
- Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, Rome, Italy
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Federica Furfaro
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Tommaso Lorenzo Parigi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier Privé Ambroise Paré—Hartmann, Paris IBD Center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy
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Mínguez A, Coello E, Garrido A, Ripoll P, Gomez M, Aguas M, Iborra M, Cerrillo E, Tortosa L, Bayarri V, Bueno N, Fernández MJ, Marqués R, Nos P, Bastida G. Optimizing outcomes with maintenance IV UST in highly bio-exposed patients with IBD. Efficacy and adjusted regimen in real world. GASTROENTEROLOGIA Y HEPATOLOGIA 2024:502253. [PMID: 39270973 DOI: 10.1016/j.gastrohep.2024.502253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/05/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND AND AIMS Ustekinumab is an effective treatment for inflammatory bowel diseases. However, some patients do not respond to conventional doses. The aim of the study was to evaluate the effectiveness of intravenous maintenance ustekinumab in patients with secondary failure. METHODS Single-center, retrospective study in adult patients with intravenous maintenance ustekinumab. The reduction of biochemical activity markers, ustekinumab trough levels and clinical indices of activity were evaluated. Biological remission was defined as the percentage decrease fecal calprotectin ≥80% and/or final fecal calprotectin ≤250 and C reactive protein <5mg/L. RESULTS Thirty-one patients were included: Crohn's disease 77.4%. All included patients were bio-exposed and 61.3% had carried ≥2 biologics. Pre-intravenous maintenance mean Harvey-Bradshaw Index was 6.5±4.38 vs 5±3.1 at week 8 (p=0.024) vs 4.1±3.1 at week 24 (p=0.019). The median ustekinumab trough level pre-intravenous maintenance was 1.40μg/ml [IQR 2.3] vs 5.35μg/ml [IQR 4.1] at week 8 (p<0.001) vs 4.8μg/ml [IQR 3.9] at week 24 (p<0.001). The pre-intravenous maintenance median fecal calprotectin was 809μg/g [IQR: 2256] vs 423μg/g [IQR: 999] at week 8 (p=0.025) vs 333μg/g [508] (p=0.001) at week 24. At the end of follow-up 48% went into biological remission. The presence of perianal disease was associated with lower biological remission (70.6% vs 27.3%, p=0.025). Median intravenous ustekinumab maintenance time was 8.55 [IQR 23.9] months. In 83.9% of patients no serious infections or malignancy were documented. CONCLUSIONS The use of maintenance intravenous ustekinumab appears to be an effective and safe strategy that can be evaluated as a salvage treatment especially in highly bio-exposed patients.
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Affiliation(s)
- Alejandro Mínguez
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.
| | - Elena Coello
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Alejandro Garrido
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Paula Ripoll
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - María Gomez
- Department of Gastroenterology, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Mariam Aguas
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Marisa Iborra
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Elena Cerrillo
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Lluis Tortosa
- IBD Research Group, IIS Hospital la Fe, Valencia, Spain
| | | | - Noemí Bueno
- IBD Research Group, IIS Hospital la Fe, Valencia, Spain
| | - Maria José Fernández
- Pharmacy Service, Digestive and Neurosciences Area, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Remedios Marqués
- Pharmacy Service, Digestive and Neurosciences Area, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Pilar Nos
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Guillermo Bastida
- IBD Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
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Li Q, Tang J, Huang ZP, Shi LS, Lyu XP, Chen XM, Chen WK, Xun AY, Guo Q, Li M, Gao X, Chao K. Clinical decision support tool-guided, selective intensive induction strategy of ustekinumab in patients with Crohn's disease: A multicenter cohort study. J Dig Dis 2024; 25:594-602. [PMID: 39710431 DOI: 10.1111/1751-2980.13318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 07/24/2024] [Accepted: 11/07/2024] [Indexed: 12/24/2024]
Abstract
OBJECTIVES We aimed to evaluate the effectiveness and safety of clinical decision support tool (CDST)-guided initial selective intensive induction therapy (IIT) for patients with Crohn's disease (CD) who were treated with ustekinumab (UST) and to identify those most likely to benefit from IIT. METHODS Patients with active CD were included in this multicenter retrospective study and were categorized as low-, intermediate-, and high-probability responders according to the UST-CDST. IIT was defined as intensive induction by two or three initial doses of weight-based intravenous UST administration. Patients treated with standard therapy (ST) served as controls. The primary end-point was corticosteroid-free clinical remission (CFCR) at Week 24. Secondary end-points included clinical remission, clinical response, endoscopic remission, endoscopic response, and C-reactive protein (CRP) normalization at Week 24. Propensity score adjustments was conducted to ensure comparability. RESULTS A total of 296 patients were included. At Week 24, IIT was associated with higher rates of CFCR (72.3% vs 43.0%, p < 0.001), clinical remission (77.3% vs 47.1%, p < 0.001), clinical response (78.1% vs 60.1%, p = 0.001), endoscopic remission (26.1% vs 9.9%, p = 0.024), and endoscopic response (58.6% vs 36.9%, p = 0.018) in low-intermediate-probability responders compared with ST. CRP normalization was comparable between groups. No significant differences were found in any end-points in high-probability responders. No serious adverse events were observed. CONCLUSION The efficacy of IIT was superior to that of ST in patients with predicted poor response to UST, which may be regarded as a novel strategy for stratifying patients at baseline.
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Affiliation(s)
- Qing Li
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jian Tang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhao Peng Huang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Li Shuo Shi
- Center for Clinical Research, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao Ping Lyu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xue Min Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Wen Ke Chen
- Department of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - An Ying Xun
- Department of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Qin Guo
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Miao Li
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Ren H, Kang J, Wang J, Su J, Zou L, Yin A, Li J, Zhou Q, Wang W, Tang Z, Zhang J, Lu Y, Yang Y, Qiu C, Ding Y, Dong W, An P. Efficacy of Ustekinumab Optimization by 2 Initial Intravenous Doses in Adult Patients With Severe Crohn's Disease. Inflamm Bowel Dis 2024; 30:1295-1302. [PMID: 37619248 DOI: 10.1093/ibd/izad184] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Although increasing studies have reported that dose escalation can improve treatment response to ustekinumab in patients with Crohn's disease (CD), their strategies mainly focus on maintenance regimen. Evidence of ustekinumab dose escalation in induction regimen, particularly in severe CD, remains limited. This study evaluated the efficacy and safety of intravenous ustekinumab with 2 initial doses in patients with severely active CD. METHODS A retrospective observational study of 99 adult patients with severe CD treated with ustekinumab from 3 IBD centers included 48 patients with standard and 51 with optimized induction treatment. Clinical outcomes, inflammatory biomarkers including fecal calprotectin (FC) normalization, and endoscopic outcomes were evaluated at weeks 16 and 48. Adverse events and treatment decisions after initial induction were also collected. RESULTS Compared with the standard group, 2 initial intravenous injections of ustekinumab achieved higher clinical response (92.2%, 47 of 51, P = .656), clinical remission (88.2%, 45 of 51, P = .221), endoscopic response (75.8%, 25 of 33, P = .125), and FC normalization (70.6%, 36 of 51, P = .138) at week 16. The mucosal healing rate at week 16 (63.6%, P = .022) was statistically higher in the optimization group. At week 48, patients with optimized treatment achieved higher clinical response (80.4%, 41 of 51, P = .003), clinical remission (70.6%, 36 of 51, P = .007), FC normalization (66.7%, 34 of 51, P = .031), endoscopic response (72.7%, 24 of 33, P = .006), and mucosal healing (57.6%, 19 of 33, P = .004). At the last follow-up, 82.4% of optimally treated patients adhered to continued treatment with ustekinumab (P < .001). CONCLUSIONS Optimization of ustekinumab by 2 initial intravenous inductions is more effective than standard therapy for adult patients with severe CD.
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Affiliation(s)
- Haixia Ren
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian Kang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jing Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Juan Su
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Liping Zou
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Anning Yin
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qian Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei Wang
- Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, Hubei Province, China
| | - Zhishun Tang
- Sports Rehabilitation, College of Sport Medicine, Wuhan Sports University, Wuhan 430079, Hubei Province, China
| | - Jing Zhang
- Department of Gastroenterology, Wuhan NO.9 Hospital, NO.20 Jilin Street, Qingshan District, Wuhan 430080, Hubei Province, China
| | - Yueyue Lu
- Department of Gastroenterology, First Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - Yuanping Yang
- Department of Gastroenterology, Yichang Central People's Hospital, Institute of Digestive Disease China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Chengen Qiu
- Sichuan Provincial People's Hospital, Chengdu 610031, China
| | - Yijuan Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Ping An
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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8
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Sturm A, Atreya R, Bettenworth D, Bokemeyer B, Dignass A, Ehehalt R, Germer CT, Grunert PC, Helwig U, Horisberger K, Herrlinger K, Kienle P, Kucharzik T, Langhorst J, Maaser C, Ockenga J, Ott C, Siegmund B, Zeißig S, Stallmach A. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) (Version 4.1) – living guideline. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1229-1318. [PMID: 39111333 DOI: 10.1055/a-2309-6123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2024]
Affiliation(s)
- Andreas Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | | | - Bernd Bokemeyer
- Gastroenterologische Gemeinschaftspraxis Minden, Minden, Deutschland
| | - Axel Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | | | | | - P C Grunert
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
| | - Ulf Helwig
- Internistische Praxengemeinschaft, Oldenburg, Deutschland
| | - Karoline Horisberger
- Universitätsmedizin Johannes Gutenberg, Universität Klinik f. Allgemein-,Visceral- und Transplantationschirurgie, Mainz, Deutschland
| | | | - Peter Kienle
- Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und Sankt Hedwig-Klinik GmbH, Mannheim, Deutschland
| | - Torsten Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Deutschland
| | - Jost Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Klinikum am Bruderwald, Bamberg, Deutschland
| | - Christian Maaser
- Gastroenterologie, Ambulanzzentrum Lüneburg, Lüneburg, Deutschland
| | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen Mitte - Gesundheit Nord, Bremen, Deutschland
| | - Claudia Ott
- Gastroenterologie Facharztzentrum, Regensburg, Deutschland
| | - Britta Siegmund
- Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Deutschland
| | - Sebastian Zeißig
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Deutschland
| | - Andreas Stallmach
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
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9
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Vernia F, Monaco S, Latella G. IBD Patients with Primary or Secondary Nonresponse to Ustekinumab Benefit from Dose Escalation or Reinduction. J Clin Med 2024; 13:3993. [PMID: 39064033 PMCID: PMC11277193 DOI: 10.3390/jcm13143993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Ustekinumab is a monoclonal antibody approved for the treatment of IBD. This drug has a well-established efficacy; however, patients may not respond or lose response. The availability of other biological therapies prompts the need for comparative data between different agents to suggest first- or second-line strategies. Aim of this review is to compare the effectiveness of ustekinumab to other biologics in Crohn's disease and ulcerative colitis, as well as report the available data on dose escalation and reinduction. A systematic electronic search of the English literature was performed up to November 2023, using Medline (PubMed), Web of Science, Scopus and the Cochrane Library. Conference proceedings were also screened. Out of 659 citations, 80 relevant articles were selected and included in the present narrative review. Head-to-head comparisons of different biological drugs are relatively scarce, mostly deriving from indirect comparison or retrospective studies. Overall available data indicate similar effectiveness in the treatment of IBD patients. Dose escalation and reinduction strategies are well documented, but the optimal treatment schedule is still to be defined. Response and remission rates vary in different studies, and a proportion of patients fail to achieve clinical and endoscopic outcomes. However, both approaches are effective and safe in nonresponders and secondary loss of response. IBD patients may benefit from dose escalation or reinduction. Both strategies prove effective in regaining response in a proportion of patients, avoiding unnecessary early switch. Head-to-head trials are still needed to determine the exact placement of this drug compared to other biologics.
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Affiliation(s)
| | | | - Giovanni Latella
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (F.V.); (S.M.)
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10
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Vootukuru N, Vasudevan A. Approach to loss of response to advanced therapies in inflammatory bowel disease. World J Gastroenterol 2024; 30:2902-2919. [PMID: 38947290 PMCID: PMC11212715 DOI: 10.3748/wjg.v30.i22.2902] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/06/2024] [Accepted: 05/28/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy. AIM To explores the issues of PNR and SLOR to non-TNFi therapies. METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM). RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response. CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.
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Affiliation(s)
- Nikil Vootukuru
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Box Hill 3128, Australia
- Eastern Health Clinical School, Monash University, Victoria, Box Hill 3128, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Box Hill 3128, Australia
- Eastern Health Clinical School, Monash University, Victoria, Box Hill 3128, Australia
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11
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Li P, Wang L, Tang Z, Wang Y, Liu Z, Ge W, Huang Y. Ustekinumab in pediatric patients with Crohn's disease: safety, and efficacy results from a multicenter retrospective study in China. Front Pediatr 2024; 12:1371322. [PMID: 38665375 PMCID: PMC11043477 DOI: 10.3389/fped.2024.1371322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Background Ustekinumab (UST) is approved as an effective therapy for Crohn's disease (CD) in adults. Off-label use is increasing in the pediatric population, more data on safety and efficacy in pediatric patients with CD is urgently needed. Aims This study aimed to evaluate the clinical efficacy and safety of UST in children and adolescents with Crohn's disease. Methods This multicenter retrospective study carried out at three tertiary care centers, and identified children who received their first dose of UST at 18 years old or younger and followed up for a minimum of 24 weeks. Data on demographics, disease behavior, location and activity, treatment history were collected. The primary outcomes were clinical remission at weeks 24-32 and weeks 48-56 of UST therapy. Secondary outcomes were clinical response at the same time points, endoscopic remission, changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin and fecal calprotectin, improvement in growth parameters, and rate of adverse events. Results Sixteen patients were included, and 11/13 (84.6%) continued to receive UST after 1 year. Our data demonstrate that the clinical remission rates were 41.7% at weeks 24∼32 with the Weighted pediatric CD activity index (wPCDAI) was lower than baseline (43.8, IQR: 31.3-51.9 vs.15, IQR: 5.6-25, p < 0.001) and 75% at weeks 48-56 with wPCDAI was lower than baseline (42.5, IQR: 23.8-50 vs. 7.5, IQR: 0-13.8, p = 0.004). Five of eleven children achieved endoscopic remission. No serious adverse events were recorded during the study period. Conclusions UST is efficacious and safe in pediatric patients with CD. Pediatric patients could benefit from UST as either a primary or secondary biologic therapy for the induction, or maintenance of remission of CD.
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Affiliation(s)
- Ping Li
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Lin Wang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Zifei Tang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Yuhuan Wang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Wensong Ge
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
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12
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Parra RS, Chebli JMF, de Azevedo MFC, Chebli LA, Zabot GP, Cassol OS, de Sá Brito Fróes R, Santana GO, Lubini M, Magro DO, Imbrizi M, Moraes ACDS, Teixeira FV, Alves Junior AJT, Gasparetti Junior NLT, da Costa Ferreira S, Queiroz NSF, Kotze PG, Féres O. Effectiveness and Safety of Ustekinumab for Ulcerative Colitis: A Brazilian Multicentric Observational Study. CROHN'S & COLITIS 360 2024; 6:otae023. [PMID: 38681979 PMCID: PMC11053358 DOI: 10.1093/crocol/otae023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Indexed: 05/01/2024] Open
Abstract
Background Real-world data on the effectiveness and safety of ustekinumab (UST) in ulcerative colitis (UC) are lacking in Latin America. In this study, we aimed to describe the effectiveness and safety of UST in a real-world multicenter cohort of Brazilian patients with UC. Methods We conducted a multicenter retrospective observational cohort study, including patients with moderate-to-severe UC (total Mayo score 6-12, with an endoscopic subscore of 2 or 3) who received UST. The co-primary endpoints were clinical remission, defined as a total Mayo score ≤2 at 1 year, with a combined rectal bleeding and stool frequency subscore of ≤1, and endoscopic remission (endoscopic Mayo subscore of 0) within 1 year from baseline. Secondary endpoints included clinical response between weeks 12 and 16, endoscopic response within 1 year of starting UST, steroid-free clinical remission at week 52, and biochemical remission at week 52. We also evaluated UST treatment persistence and safety. Results A total of 50 patients were included (female, n = 36, 72.0%), with a median disease duration of 9.2 years (1-27). Most patients had extensive colitis (n = 38, 76.0%), and 43 (86.0%) were steroid dependent at baseline. Forty patients (80.0%) were previously exposed to biologics (anti-TNF drugs, n = 31; vedolizumab [VDZ], n = 27). The co-primary endpoints of clinical remission at 1 year and endoscopic remission within 1 year were achieved by 50.0% and 36.0% of patients, respectively. Clinical response at weeks 12-16 was 56.0%, and endoscopic response, steroid-free clinical remission, and biochemical remission at week 52 were 68.0%, 46.5%, and 50.0%, respectively. The UST treatment persistence rate at 24 months was 73.7%. During the follow-up, 10 patients (20.0%) were hospitalized, mostly due to disease progression, and 3 patients required colectomy. Nine patients (18.0%) discontinued the drug mainly due to a lack of effectiveness. Twenty-seven adverse events (AEs) were reported, 16 of which were considered as serious AEs. Conclusions In this real-world cohort of difficult-to-treat UC patients, UST was associated with improvements in clinical, biochemical, and endoscopic outcomes. The safety profile was favorable, consistent with the known profile of UST.
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Affiliation(s)
- Rogério Serafim Parra
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Júlio Maria Fonseca Chebli
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | | | - Liliana Andrade Chebli
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | - Gilmara Pandolfo Zabot
- Department of Colon and Rectum Surgery, Moinhos de Vento Hospital, Feevale University, Porto Alegre, Brazil
| | - Ornella Sari Cassol
- Department of Colorectal Surgery, Hospital de Clínicas de Passo Fundo, Atitus Medical School, Rio Grande do Sul, Brazil
| | | | | | - Márcio Lubini
- Department of Surgery, Passo Fundo University, Rio Grande do Sul, Brazil
| | - Daniela Oliveira Magro
- Department of Surgery, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Marcello Imbrizi
- Department of Surgery, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | | | | | | | | | - Sandro da Costa Ferreira
- Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Natália Sousa Freitas Queiroz
- Health Sciences Graduate Program, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil
- IBD Center, Santa Cruz Hospital, Curitiba, Brazil
- Internal Medicine Department, Hospital Copa D´Or, Rio de Janeiro, Brazil
| | - Paulo Gustavo Kotze
- Health Sciences Graduate Program, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil
- Department of Colorectal Surgery, Hospital de Clínicas de Passo Fundo, Atitus Medical School, Rio Grande do Sul, Brazil
| | - Omar Féres
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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13
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Dalal RS, Sharma PP, Bains K, Pruce JC, Allegretti JR. 1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure. Inflamm Bowel Dis 2024; 30:395-401. [PMID: 37209416 DOI: 10.1093/ibd/izad087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Indexed: 05/22/2023]
Abstract
BACKGROUND Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. METHODS In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. RESULTS Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). CONCLUSIONS In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.
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Affiliation(s)
- Rahul S Dalal
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Kanwal Bains
- Department of Nutrition, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jordan C Pruce
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jessica R Allegretti
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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14
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Suárez Ferrer C, Arroyo Argüelles J, Rueda García JL, García Ramírez L, Martin Arranz E, Sánchez Azofra M, Poza Cordón J, Noci Belda J, Martin-Arranz MD. Intensification with Intravenous Ustekinumab in Refractory Crohn's Disease. J Clin Med 2024; 13:669. [PMID: 38337361 PMCID: PMC10856525 DOI: 10.3390/jcm13030669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/14/2024] [Accepted: 01/15/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND The rates of clinical and biochemical responses in Crohn's disease (CD) patients treated with intravenous (IV) ustekinumab (UST) intensification are scarcely described. METHODS Patients with diagnosis of CD who were under intensified IV ustekinumab treatment (130 mg every 4 weeks) were retrospectively included, evaluating the clinical and biochemical response 12 weeks after the change in treatment regimen (switch from SC to IV), as well as the serum levels of the drug. RESULTS Twenty-seven patients, all of whom had transitioned to intensified intravenous ustekinumab treatment due to a secondary loss of response to the drug, were included in the retrospective analysis. At the baseline visit, prior to changing IV UST, differences in levels were observed between intensified and non-intensified patients (7216 vs. 2842 ng/mL, p = 0.00005). However, no significant differences were found between these two groups 12 weeks after IV intensification (7949 vs. 7937 ng/mL; p = 0.99). In patients with previous intensified UST SC, a decrease in fecal calprotectin was observed 12 weeks after starting IV intensification, going from a mean of 1463 ug/g to 751 ug/g, although the differences were not significant (p = 0.14). CONCLUSION In our experience, intensifying treatment with IV UST leads to clinical and biochemical improvements in CD patients with a secondary loss of response to SC maintenance with this drug, and an increase in drug levels was observed 12 weeks after IV UST intensification.
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Affiliation(s)
- Cristina Suárez Ferrer
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - José Arroyo Argüelles
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
| | - Jose Luis Rueda García
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - Laura García Ramírez
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - Eduardo Martin Arranz
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - María Sánchez Azofra
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - Joaquín Poza Cordón
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
| | - Jesús Noci Belda
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
| | - Maria Dolores Martin-Arranz
- Inflammatory Bowel Disease Unit, Digestive Medicine Service, Hospital Universitario La Paz, 28046 Madrid, Spain; (J.A.A.); (L.G.R.); (E.M.A.); (M.S.A.); (M.D.M.-A.)
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, 28049 Madrid, Spain
- Faculty de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain
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15
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Olmedo Martín RV, Vázquez Morón JM, Martín Rodríguez MDM, Lázaro Sáez M, Hernández Martínez Á, Argüelles-Arias F. Effectiveness and safety of ustekinumab dose escalation in Crohn's disease: a multicenter observational study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:686-692. [PMID: 37314131 DOI: 10.17235/reed.2023.9402/2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
BACKGROUND ustekinumab has proven effective in Crohn's disease (CD). However, some patients will partially respond or lose response over time. Data supporting the effectiveness of dose escalation in this scenario is scarce. AIM to evaluate the effectiveness of ustekinumab dose escalation in CD. METHODS patients with active CD (Harvey-Bradshaw ≥ 5) who had received intravenous (IV) induction and at least a subcutaneous (SC) dose were included in this retrospective observational study. Ustekinumab dose was escalated, either via shortening of the interval to six or four weeks or IV reinduction plus shortening to every four weeks. RESULTS ninety-one patients were included, and ustekinumab dose was escalated after a median of 35 weeks of treatment. At week 16 after intensification, steroid-free clinical response and remission were observed in 62.6 % and 25.3 % of patients, respectively. Systemic corticosteroids were discontinued in 46.7 % of patients who were on corticosteroids at baseline. Follow-up data beyond week 16 were available for 78 % of patients; at the last visit, 66.2 % and 43.7 % were in steroid-free clinical response and remission, respectively. After a median follow-up of 64 weeks, 81 % of patients were still treated with ustekinumab. Adverse events were reported in 4.3 % of patients; these were all mild and did not lead to hospitalization or discontinuation of treatment. Five patients (5.5 %) underwent surgical resection, with no immediate postsurgical complications. CONCLUSION ustekinumab dose escalation was effective in recapturing response in over half of the patients. These findings suggest that dose escalation should be considered in patients who experience loss or partial response to the standard maintenance.
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Ebihara S, Urashima T, Amano W, Yamamura H, Konishi N. Macrophage polarization toward M1 phenotype in T cell transfer colitis model. BMC Gastroenterol 2023; 23:411. [PMID: 38012544 PMCID: PMC10680295 DOI: 10.1186/s12876-023-03054-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/18/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND T cell transfer colitis model is often used to study the CD4+ T cell functions in the intestine. However, the specific roles of macrophages in colitis remain unclear. In this study, we aimed to evaluate the phenotype and functions of macrophages in the colonic lamina propria (LP) in a colitis model. METHODS Colitis was induced in scid mice via the adaptive transfer of CD4+CD45RBhi T cells. Then, flow cytometry was used to determine the number of macrophages in the colonic LP and expression of cytokines in macrophages at the onset of colitis. Moreover, M1/M2 macrophage markers were detected in the colonic LP during colitis development using high-dimensional single-cell data and gating-based analyses. Expression levels of M1 markers in macrophages isolated from the colonic LP were measured using quantitative reverse transcription-polymerase chain reaction. Additionally, macrophages were co-cultured with T cells isolated from the colon to assess colitogenic T cell activation. RESULTS Infiltration of macrophages into the colon increased with the development of colitis in the T cell transfer colitis model. M1/M2 macrophage markers were observed in this model, as observed in the colon of patients with inflammatory bowel disease (IBD). Moreover, number of M1 macrophages increased, whereas that of M2 macrophages decreased in the colonic LP during colitis development. M1 macrophages were identified as the main source of inflammatory cytokine production, and colitogenic T cells were activated via interactions with these macrophages. CONCLUSIONS Our findings revealed that macrophages polarized toward the M1 phenotype in LP during colitis development in the T cell transfer colitis model. Therefore, the colitis model is suitable for the evaluation of the efficacy of macrophage-targeted drugs in human IBD treatment. Furthermore, this model can be used to elucidate the in vivo functions of macrophages in the colon of patients with IBD.
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Affiliation(s)
- Shin Ebihara
- Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco, Inc, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Toshiki Urashima
- Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco, Inc, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan
| | - Wataru Amano
- Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco, Inc, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan
| | - Hideto Yamamura
- Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco, Inc, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan
| | - Noriko Konishi
- Biological/Pharmacological Research Laboratories, Takatsuki Research Center, Central Pharmaceutical Research Institute, Japan Tobacco, Inc, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan
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17
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Pauwels RWM, Ten Bokkel Huinink S, van der Woude CJ, Doukas M, Oudijk L, de Vries AC. Early fecal calprotectin levels at week 8 may guide therapeutic decisions on Ustekinumab therapy in patients with Crohn's disease. Scand J Gastroenterol 2023; 58:980-987. [PMID: 36970968 DOI: 10.1080/00365521.2023.2194009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/12/2023] [Accepted: 03/19/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND Response evaluation after induction therapy with ustekinumab (UST) in Crohn's disease (CD) is important for decisions on maintenance therapy. We aimed to assess the potential of fecal calprotectin (FC) levels to predict endoscopic response at week 16. METHODS CD patients with FC >100 µg/g and endoscopic active disease (SES-CD> 2, Rutgeerts' score ≥ i2) at initiation of UST therapy were enrolled. FC was determined at weeks 0, 2, 4, 8 and 16 and patients underwent a colonoscopy at week 16. The primary outcome was an endoscopic response at week 16 (SES-CD score ≥50% decrease or a decrease of ≥1 points in Rutgeerts' score). The optimal cut-off levels of FC and change in FC to predict endoscopic response were determined using ROC statistics. RESULTS 59 CD patients were included. Endoscopic response was observed in 21/59 (36%) patients. The diagnostic accuracy for FC levels at week 8 to predict endoscopic response at week 16 showed a predictive value of 0.71. A decrease in FC levels ≥500 µg/g between baseline at week 8 indicates endoscopic response (PPV = 89%), whereas absence of any decrease indicates endoscopic non-response after induction (NPV = 81%). CONCLUSIONS Continuation of UST therapy without endoscopic response evaluation may be considered in patients with a decrease in FC levels of ≥500 µg/g at week 8. The decision on continuation of UST therapy or therapy optimization needs reconsideration in patients without a decrease of FC level. In all other patients, endoscopic response evaluation of induction therapy remains essential for therapeutic decisions.
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Affiliation(s)
- Renske W M Pauwels
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - M Doukas
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - L Oudijk
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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18
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Hermida Pérez B, Mancebo Mata A, de Jorge Turrión MÁ, Varela Trastoy P. Efficacy and safety of intravenous ustekinumab maintenance therapy in Crohn's disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 116. [PMID: 36975146 DOI: 10.17235/reed.2023.9594/2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Crohn's disease is a chronic multifactorial disease for which therapeutic options have expanded in the last decades. However there are still patients who lack or lose response to current standard treatment strategies. A unicentric, retrospective, study was performed in order to evaluate the clinical and biochemical response to intravenous ustekinumab manteinance therapy (IVUMT) in patients with refractory CD. We included 12 patients from our centre who started IVUMT between September 2018 and November 2021. 75% started IV treatment after previous subcutaneous (SC) treatment. At week 8 (n=8), 63% had clinical response, with 25% in clinical remission. At week 16 (n=10), 60% had clinical response, with 50% in clinical remission. At week 26 (n=10), 90% had clinical response, with 60% in clinical remission. At week 52 (n=11), 91% had clinical response, with 64% in clinical remission (Fig. 2). Basal faecal calprotectin (FCP) median level was 684µg/g, with a significant reduction at 52 weeks, with median FCP 97µg/g (p=0,017). Basal C-reactive protein (CRP) median level was 11,6mg/L. A significant reduction was observed at week 26, with median CRP 2,8mg/L (p=0,008); and 52 weeks, with median CRP 2,7 (p=0,013). Average follow-up was 117,1 weeks, average treatment survival was 105,9 weeks. There were no severe adverse events. Our results suggest IVUMT is a safe and effective treatment for most patients with refractory and complex CD and should be considered as an option in selected patients.
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19
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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20
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Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2022; 75:717-723. [PMID: 36084231 DOI: 10.1097/mpg.0000000000003608] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.
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21
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Chaparro M, Baston-Rey I, Fernández-Salgado E, González García J, Ramos L, Diz-Lois Palomares MT, Argüelles-Arias F, Iglesias Flores E, Cabello M, Rubio Iturria S, Núñez Ortiz A, Charro M, Ginard D, Dueñas Sadornil C, Merino Ochoa O, Busquets D, Iyo E, Gutiérrez Casbas A, Ramírez de la Piscina P, Boscá-Watts MM, Arroyo M, García MJ, Hinojosa E, Gordillo J, Martínez Montiel P, Velayos Jiménez B, Quílez Ivorra C, Vázquez Morón JM, María Huguet J, González-Lama Y, Muñagorri Santos AI, Amo VM, Martín-Arranz MD, Bermejo F, Martínez Cadilla J, Rubín de Célix C, Fradejas Salazar P, San Román AL, Jiménez N, García López S, Figuerola A, Jiménez I, Martínez Cerezo FJ, Taxonera C, Varela P, de Francisco R, Monfort D, Molina Arriero G, Hernández Camba A, García-Alonso FJ, Van Domselaar M, Pajares Villarroya R, Núñez A, Rodríguez Moranta F, Marín-Jiménez I, Robles Alonso V, Martín Rodríguez MDM, Camo-Monterde P, García Tercero I, Navarro Llavat M, Arias García L, Hervías Cruz D, Sulleiro S, Novella C, Vispo E, Barreiro-de Acosta M, Gisbert JP. Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients: The SUSTAIN Study. Inflamm Bowel Dis 2022; 28:1725-1736. [PMID: 35166347 DOI: 10.1093/ibd/izab357] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn's disease (CD) patients in real-world clinical practice. METHODS A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. RESULTS A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). CONCLUSIONS Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.
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Affiliation(s)
- María Chaparro
- Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Iria Baston-Rey
- Gastroenterology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
| | | | | | - Laura Ramos
- Gastroenterology Department, Hospital Universitario de Canarias, Tenerife, Spain
| | | | - Federico Argüelles-Arias
- Gastroenterology Department, Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - Eva Iglesias Flores
- Gastroenterology Department, Hospital Universitario Reina Sofía, Universidad de Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain
| | - Mercedes Cabello
- Gastroenterology Department, Hospital Universitario Virgen de Valme, Seville, Spain
| | - Saioa Rubio Iturria
- Gastroenterology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Andrea Núñez Ortiz
- Gastroenterology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Mara Charro
- Gastroenterology Department, Hospital de Barbastro, Barbastro, Spain
| | - Daniel Ginard
- Gastroenterology Department, Hospital Universitario Son Espases, Palma, Spain
| | | | - Olga Merino Ochoa
- Gastroenterology Department, Hospital Universitario Cruces, Barakaldo, Spain
| | - David Busquets
- Gastroenterology Department, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain
| | - Eduardo Iyo
- Gastroenterology Department, Hospital Comarcal de Inca, Inca, Spain
| | - Ana Gutiérrez Casbas
- Gastroenterology Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | | | - Marta Maia Boscá-Watts
- Gastroenterology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Maite Arroyo
- Gastroenterology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - María José García
- Gastroenterology Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitario Valdecilla (IDIVAL), Santander, Spain
| | - Esther Hinojosa
- Gastroenterology Department, Hospital de Manises, Manises, Spain
| | - Jordi Gordillo
- Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Benito Velayos Jiménez
- Gastroenterology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | | | | | - José María Huguet
- Gastroenterology Department, Hospital General Universitario de Valencia, Valencia, Spain
| | - Yago González-Lama
- Gastroenterology Department, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
| | | | - Víctor Manuel Amo
- Gastroenterology Department, Hospital Regional de Málaga, Málaga, Spain
| | - María Dolores Martín-Arranz
- Gastroenterology Department, Hospital Universitario de La Paz, Institute for Health Research La Paz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Fernando Bermejo
- Gastroenterology Department, Instituto de Investigación Sanitaria del Hospital La Paz, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | | | - Cristina Rubín de Célix
- Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | | | | | - Nuria Jiménez
- Gastroenterology Department, Hospital General Universitario de Elche, Elche, Spain
| | | | - Anna Figuerola
- Gastroenterology Department, Hospital General Universitario de Castellón, Castellón de la Plana, Spain
| | - Itxaso Jiménez
- Gastroenterology Department, Hospital Universitario de Galdakao-Usansolo, Galdakao, Spain
| | | | - Carlos Taxonera
- Gastroenterology Department, Instituto de Investigación del Hospital Clínico San Carlos, Hospital Clínico Universitario San Carlos, Madrid, Spain
| | - Pilar Varela
- Gastroenterology Department, Hospital Universitario de Cabueñes, Gijón, Spain
| | - Ruth de Francisco
- Gastroenterology Department, Instituto de Investigación Biosanitaria del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - David Monfort
- Gastroenterology Department, Consorci Sanitari de Terrassa, Terrassa, Spain
| | - Gema Molina Arriero
- Gastroenterology Department, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain
| | - Alejandro Hernández Camba
- Gastroenterology Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | | | - Manuel Van Domselaar
- Gastroenterology Department, Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain
| | | | - Alejandro Núñez
- Gastroenterology Department, Hospital Clínico Universitario de Salamanca, Salamanca, Spain
| | | | - Ignacio Marín-Jiménez
- Servicio de Aparato Digestivo, IiSGM, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | | | | | | | - Iván García Tercero
- Gastroenterology Department, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Mercedes Navarro Llavat
- Gastroenterology Department, Hospital de Sant Joan Despí Moisès Broggi, Sant Joan Despí, Spain
| | - Lara Arias García
- Gastroenterology Department, Hospital Universitario de Burgos, Burgos, Spain
| | - Daniel Hervías Cruz
- Gastroenterology Department, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | | | | | | | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
| | - Javier P Gisbert
- Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
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Dalal RS, Esckilsen S, Barnes EL, Pruce JC, Marcus J, Allegretti JR. Predictors and Outcomes of Ustekinumab Dose Intensification in Ulcerative Colitis: A Multicenter Cohort Study. Clin Gastroenterol Hepatol 2022; 20:2399-2401.e4. [PMID: 33775893 PMCID: PMC8464615 DOI: 10.1016/j.cgh.2021.03.028] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023]
Abstract
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.
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Affiliation(s)
- Rahul S Dalal
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Scott Esckilsen
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Edward L Barnes
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jordan C Pruce
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jenna Marcus
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jessica R Allegretti
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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23
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Castro PCSD, Magro DO, Nones RB, Furlan TK, Miranda EF, Kotze PG. USTEKINUMAB IN CROHN'S DISEASE MANAGEMENT: A BRAZILIAN OBSERVATIONAL STUDY. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:S0004-28032022005001206. [PMID: 36515346 DOI: 10.1590/s0004-2803.202204000-89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Real-world data on the use of Ustekinumab (UST) in Brazilian and Latin American patients with Crohn's disease (CD) are scarce. OBJECTIVE The primary endpoint was assessment of clinical remission at weeks 8 and 52, and secondary endpoints were: assessment of clinical response at weeks 8 and 52, endoscopic remission, adverse events, and rates of CD-related abdominal surgery during follow-up. METHODS observational and retrospective study, including patients with CD treated at two centers, who received UST at any time during their treatment. Remission and clinical response were defined as a Harvey-Bradshaw index ≤4 and ≥3 points reduction, respectively. RESULTS Seventy-four patients were included, 85.1% previously exposed to anti-TNFs. Clinical remission was observed in 45.8% and 59.4% of patients at weeks 8 and 52, respectively. The clinical response rates were 54.2% and 67.6% at weeks 8 and 52. Endoscopic remission was observed in 21.8% of patients. Seventeen patients had adverse events, mostly mild infections, with 22.9% of patients undergoing abdominal surgery (ileocolectomy being the most common procedure). CONCLUSION UST therapy resulted in significant rates of remission and clinical response, as described in other real-world studies. Few patients had adverse events during treatment, showing its adequate safety profile.
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Affiliation(s)
- Paula Cenira Senger de Castro
- Pontifícia Universidade Católica do Paraná, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Curitiba, PR, Brasil
| | - Daniéla Oliveira Magro
- Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Cirurgia, Campinas, PR, Brasil
| | - Rodrigo Bremer Nones
- Pontifícia Universidade Católica do Paraná, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Curitiba, PR, Brasil
| | - Thaisa Kowalski Furlan
- Universidade Federal do Paraná, Hospital de Clínicas, Departamento de Gastroenterologia, Curitiba, PR, Brasil
| | - Eron Fábio Miranda
- Pontifícia Universidade Católica do Paraná, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Curitiba, PR, Brasil
| | - Paulo Gustavo Kotze
- Pontifícia Universidade Católica do Paraná, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde, Curitiba, PR, Brasil
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Andres B, Taleban S. Exacerbation of Atopic Dermatitis Associated with Ustekinumab Treatment in Crohn's Disease. Cureus 2022; 14:e29718. [PMID: 36320969 PMCID: PMC9617006 DOI: 10.7759/cureus.29718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Ustekinumab inhibits interleukins 12 and 23 and modulates the T helper cell-mediated immune response of Crohn's disease. However, ustekinumab may also exacerbate atopic disease by increasing the T helper 2 cell-mediated pathway. We present the first known case of exacerbation of atopic dermatitis in a patient with Crohn's disease receiving ustekinumab. Additional associations in dose frequency, peripheral eosinophilia, and elevated serum IgE were observed. However, while novel in Crohn's disease, exacerbation of atopy after ustekinumab infusion has been observed in patients with psoriasis and psoriatic arthritis.
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Pugliese D, Privitera G, Fiorani M, Parisio L, Calvez V, Papa A, Gasbarrini A, Armuzzi A. Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab. Therap Adv Gastroenterol 2022; 15:17562848221102283. [PMID: 35721840 PMCID: PMC9201364 DOI: 10.1177/17562848221102283] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/04/2022] [Indexed: 02/06/2023] Open
Abstract
As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.
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Affiliation(s)
- Daniela Pugliese
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy
| | - Giuseppe Privitera
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Marcello Fiorani
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Laura Parisio
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy
| | - Valentin Calvez
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Alfredo Papa
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy,Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Antonio Gasbarrini
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy,Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
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Parra RS, Chebli JMF, Queiroz NSF, Damião AOMC, de Azevedo MFC, Chebli LA, Bertges ER, Alves Junior AJT, Ambrogini Junior O, da Silva BLPS, Lubini M, Bafutto M, Flores C, Vilela EG, Boratto SF, Gasparetti Junior NLT, Steinwurz F, Carvalho NS, Féres O, da Rocha JJR. Long-term effectiveness and safety of ustekinumab in bio-naïve and bio-experienced anti-tumor necrosis factor patients with Crohn's disease: a real-world multicenter Brazilian study. BMC Gastroenterol 2022; 22:199. [PMID: 35448949 PMCID: PMC9027080 DOI: 10.1186/s12876-022-02280-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 04/12/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The effectiveness of ustekinumab (UST) in the treatment of Crohn's disease (CD) has been demonstrated in the pivotal Phase 3 UNITI 1 and 2 and IM-UNITI studies in both anti-TNF-naïve and anti-TNF-exposed patients. Given the selective nature of pivotal trial designs, real-world effectiveness and safety studies are warranted. We report our experience with UST treatment in a large, real-world multicenter cohort of Brazilian patients with CD. METHODS We performed a retrospective multicenter study including patients with CD, predominantly biologically refractory CD, who received UST. The primary endpoint was the proportion of patients in clinical remission at weeks 8, 24 and 56. Possible predictors of clinical and biological response/remission and safety outcomes were also assessed. RESULTS Overall, 245 CD (mean age 39.9 [15-87]) patients were enrolled. Most patients (86.5%) had been previously exposed to biologics. According to nonresponder imputation analysis, the proportions of patients in clinical remission at weeks 8, 24 and 56 were 41.0% (n = 98/239), 64.0% (n = 153/239) and 39.3% (n = 94/239), respectively. A biological response was achieved in 55.4% of patients at week 8, and 59.3% were in steroid-free remission at the end of follow-up. No significant differences in either clinical or biological remission were noted between bio-naïve and bio-experienced patients. Forty-eight patients (19.6%) presented 60 adverse events during the follow-up, of which 8 (13.3%) were considered serious adverse events (3.2% of 245 patients). Overall, a proximal disease location, younger age, perianal involvement, and smoking were associated with lower rates of clinical remission over time. CONCLUSIONS UST therapy was effective and safe in the long term in this large real-life cohort of Brazilian patients with refractory CD, regardless of previous exposure to other biological agents.
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Affiliation(s)
- Rogério Serafim Parra
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP, Zip code: 14048-900, Brazil.
| | | | | | | | | | | | | | | | | | | | | | | | - Cristina Flores
- Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | | | | | | | - Omar Féres
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP, Zip code: 14048-900, Brazil
| | - José Joaquim Ribeiro da Rocha
- Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP, Zip code: 14048-900, Brazil
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Sturm A, Atreya R, Bettenworth D, Bokemeyer B, Dignaß A, Ehehalt R, Germer C, Grunert PC, Helwig U, Herrlinger K, Kienle P, Kreis ME, Kucharzik T, Langhorst J, Maaser C, Ockenga J, Ott C, Siegmund B, Zeißig S, Stallmach A. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – August 2021 – AWMF-Registernummer: 021-004. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:332-418. [PMID: 35263784 DOI: 10.1055/a-1713-3941] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Andreas Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Deutschland
| | | | - Bernd Bokemeyer
- Gastroenterologische Gemeinschaftspraxis Minden, Deutschland
| | - Axel Dignaß
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | | | - Christoph Germer
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Deutschland
| | - Philip C Grunert
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
| | - Ulf Helwig
- Internistische Praxengemeinschaft, Oldenburg, Deutschland
| | | | - Peter Kienle
- Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und Sankt Hedwig-Klinik GmbH, Mannheim, Deutschland
| | - Martin E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Deutschland
| | - Torsten Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Deutschland
| | - Jost Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Klinikum am Bruderwald, Bamberg, Deutschland
| | | | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen Mitte - Gesundheit Nord, Bremen, Deutschland
| | - Claudia Ott
- Gastroenterologie Facharztzentrum, Regensburg, Deutschland
| | - Britta Siegmund
- Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Deutschland
| | - Sebastian Zeißig
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Deutschland
| | - Andreas Stallmach
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
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Yzet C, Brazier F, Sabbagh C, Fumery M. Managing complex perianal disease after anti-TNF failure: Where to go next? CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100081. [PMID: 35106477 PMCID: PMC8784625 DOI: 10.1016/j.crphar.2022.100081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 12/05/2022] Open
Abstract
Crohn's disease is a chronic inflammatory bowel disease that affects various intestinal segments and can involve the perianal region. Although anti-tumor necrosis factor (TNF) agents have revolutionized the management of Crohn's disease and improved the prognosis for patients with perianal Crohn's disease (pCD), their long-term effectiveness is limited: over 60% of patients relapse after one year of maintenance therapy. In recent years, significant advances have been made in the treatment of complex perianal fistulas after anti-TNF failure. Concomitant treatment with antibiotics and immunosuppressants improves the effectiveness of anti-TNF agents. Therapeutic drug monitoring and dose adjustment of anti-TNF therapy (targeting a higher trough level) might also improve treatment response. Novel therapeutic strategies might provide new opportunities for pCD management; for example, ustekinumab might be effective after anti-TNF treatment failure, although more studies are needed. As suggested in recent international guidelines, mesenchymal stem cell injection might be an effective, safe treatment for complex pCD.
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Affiliation(s)
- Clare Yzet
- Gastroenterology Unit, Amiens University Medical Center and Jules Verne University of Picardie, Amiens, France
| | - Franck Brazier
- Gastroenterology Unit, Amiens University Medical Center and Jules Verne University of Picardie, Amiens, France
| | - Charles Sabbagh
- Digestive Surgery Unit, Amiens University Medical Center and Jules Verne University of Picardie, Amiens, France
| | - Mathurin Fumery
- Gastroenterology Unit, Amiens University Medical Center and Jules Verne University of Picardie, Amiens, France
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Heron V, Li Fraine S, Panaccione N, Restellini S, Germain P, Candido K, Bernstein CN, Bessissow T, Bitton A, Chauhan UK, Lakatos PL, Marshall JK, Michetti P, Seow CH, Rosenfeld G, Panaccione R, Afif W. OUP accepted manuscript. J Can Assoc Gastroenterol 2022; 5:208-213. [PMID: 36196277 PMCID: PMC9527659 DOI: 10.1093/jcag/gwac017] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background/Aims Methods Results Conclusions
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Affiliation(s)
- Valerie Heron
- Division of Gastroenterology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Steven Li Fraine
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Nicola Panaccione
- Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AlbertaCanada
| | - Sophie Restellini
- Division of Gastroenterology and Hepatology, Geneva’s University Hospitals and University of Geneva, Switzerland
| | - Pascale Germain
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Kristina Candido
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Charles N Bernstein
- Department of Medicine, Section of Gastroenterology, Max Rady College of Medicine, Rad Faculty of Health Sciences, University of Manitoba, and the University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada
| | - Talat Bessissow
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Alain Bitton
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - Usha K Chauhan
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Peter L Lakatos
- Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - John K Marshall
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Pierre Michetti
- Gastroenterology Beaulieu and Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland
| | - Cynthia H Seow
- Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AlbertaCanada
| | - Greg Rosenfeld
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Remo Panaccione
- Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AlbertaCanada
| | - Waqqas Afif
- Correspondence: Waqqas Afif, MD, FRCPC, Associate Professor of Medicine, Division of Gastroenterology, McGill University Health Center, Montreal General Hospital, 1650 Ave. Cedar, C7-200, Montreal, QC, H3G 1A4, e-mail:
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Annese V, Nathwani R, Alkhatry M, Al-Rifai A, Al Awadhi S, Georgopoulos F, Jazzar AN, Khassouan AM, Koutoubi Z, Taha MS, Limdi JK. Optimizing biologic therapy in inflammatory bowel disease: a Delphi consensus in the United Arab Emirates. Therap Adv Gastroenterol 2021; 14:17562848211065329. [PMID: 34987611 PMCID: PMC8721421 DOI: 10.1177/17562848211065329] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic, relapsing-remitting inflammatory conditions with a substantial negative impact on health-related quality of life and work productivity. Treatment of IBD has been revolutionized by the advent of biologic therapies, initially with anti-TNF agents and more recently with multiple alternatives targets, and yet more under development. OBJECTIVES Approximatively one third of patients do not respond to biologic therapy and more importantly a significant proportion experiences partial response or loss of response during treatment. The latter are common clinical situations and paradoxically are not addressed in the commercial drug labels and available guidelines. There is therefore a clinical need for physicians to understand when and how eventually to optimize the biologic therapy. DESIGN This consensus using a Delphi methodology was promoted and supported by the Emirates Society of Gastroenterology and Hepatology to close this gap. DATA SOURCES AND METHODS Following an extensive systematic review of over 60,000 studies, 81 studies with dose escalation and five addressing drug monitoring were selected and in addition five systematic reviews and three guidelines. RESULTS AND CONCLUSION after three rounds of voting 18 statements were selected with agreement ranging from of 80% to 100.
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Affiliation(s)
| | - Rahul Nathwani
- Department of Gastroenterology, Mediclinic City Hospital, Mohammed Bin Rashid University, Dubai, United Arab Emirates
| | - Maryam Alkhatry
- Gastroenterology and Endoscopy Department, Ibrahim Bin Hamad Obaid Allah Hospital, Ministry of Health and Prevention, Ras Al Khaimah, United Arab Emirates
| | - Ahmad Al-Rifai
- Department of Gastroenterology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Sameer Al Awadhi
- Digestive Disease Unit, Rashid Hospital, Dubai, United Arab Emirates
| | - Filippos Georgopoulos
- Gastroenterology and Endoscopy Unit, Al Zahra Hospital Dubai, Dubai, United Arab Emirates
| | - Ahmad N. Jazzar
- Gastroenterology Division, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | | | - Zaher Koutoubi
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Mazen S. Taha
- Gastroenterology and Hepatology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Jimmy K. Limdi
- Department of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester Academic Health Sciences, University of Manchester, Manchester, UK
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Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease. Eur J Gastroenterol Hepatol 2021; 33:e831-e836. [PMID: 34402470 DOI: 10.1097/meg.0000000000002275] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSION 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.
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Yao JY, Zhang M, Wang W, Peng X, Zhao JZ, Liu T, Li ZW, Sun HT, Hu P, Zhi M. Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn's disease: a Chinese real-world study. BMC Gastroenterol 2021; 21:380. [PMID: 34663208 PMCID: PMC8522105 DOI: 10.1186/s12876-021-01946-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/28/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Ustekinumab (UST), a newly-used biologic targeting p40 subunit of IL12 and IL23 in China, exerts a confirmed therapeutic effect on the induction and maintenance therapies for refractory Crohn's disease (CD). Therapeutic drug monitoring based on trough and antibody concentration is of core importance when treating patients who lose response to UST. We aimed to analyze the UST exposure-response relationship in CD treatment in the real-world setting. METHODS We retrospectively enrolled patients with CD who received UST between March 1, 2020 and May 31, 2021, at the inflammatory bowel disease (IBD) center of the Sun Yat-Sun Affiliated Sixth Hospital. Baseline characteristic information, biomarker examination, clinical outcomes determined by the Crohn's disease activity index (CDAI), and endoscopic outcomes evaluated using a simple endoscopic score for Crohn's disease (SES-CD) at week 16/20 were collected. The optimal UST cut-off trough concentration was identified using receiver operating characteristic curve (ROC) analysis. RESULTS Nineteen eligible patients were included in the study, the mean age was 29.1 ± 9.1 years and the mean disease duration was 5.5 ± 4.7 years. At the initiation of the study, 89.5% of the patients had been exposed to prior biologics, 42.1% had previous CD-related surgeries, and 52.6% had perianal diseases. At week 16/20 after the UST initiation, clinical response, clinical remission, endoscopic response, and endoscopic remission were 89.5%, 84.2%, 42.2%, and 73.7%, respectively. The cut-off optimal trough concentration for UST was 1.12 μg/mL, as determined by the ROC with an area under the curve (AUC) of 0.78, sensitivity of 87.5%, and specificity of 72.7%. Patients with a UST trough concentration > 1.12 μg/mL had a significantly higher rate of endoscopic remission than those without (70.0% vs. 11.1%, P = 0.02). CONCLUSIONS UST is an effective therapeutic option for refractory CD treatment. A UST trough concentration above 1.12 μg/mL was associated with endoscopic remission at week 16/20 after UST initiation. Trial registration This study was approved and retrospectively registered by the Ethics Committee of Sun Yat-Sen University (2021ZSLYEC-066, March 29, 2021) and the Clinical Trial Registry (NCT04923100, June 10, 2021).
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Affiliation(s)
- Jia-Yin Yao
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Min Zhang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Wei Wang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Xiang Peng
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Jun-Zhang Zhao
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Tao Liu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Zhi-Wei Li
- Department of Medical Statistics, University of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Hai-Tian Sun
- Special Inspection Project Department, Guangzhou Huayin Medical Examination Center, Guangzhou, Guangdong Province, China
| | - Pinjin Hu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China
| | - Min Zhi
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, 510655, Guangdong Province, China.
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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Fumery M, Filippi J, Abitbol V, Biron A, Laharie D, Serrero M, Altwegg R, Bouhnik Y, Peyrin-Biroulet L, Gilletta C, Roblin X, Pineton de Chambrun G, Vuitton L, Bourrier A, Nancey S, Gornet JM, Nahon S, Bouguen G, Viennot S, Nachury M, Amiot A. Effectiveness and safety of ustekinumab maintenance therapy in 103 patients with ulcerative colitis: a GETAID cohort study. Aliment Pharmacol Ther 2021; 54:944-951. [PMID: 34296456 DOI: 10.1111/apt.16544] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/10/2021] [Accepted: 07/11/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Phase III trials have demonstrated the efficacy and safety of ustekinumab in ulcerative colitis (UC), but few real-life long-term data are currently available. AIMS To assess the real-world effectiveness and safety of ustekinumab in patients with UC. METHODS From January to September 2019, all consecutive patients with active UC treated with ustekinumab in a GETAID centre were included. Patients were evaluated at week 52. Remission was defined as a partial Mayo Clinic score ≤2. RESULTS We included 103 patients with UC (62 men; mean age: 41.2 ± 16.2 years; 52% pancolitis E3) with an insufficient response to immunosuppressants, anti-TNFs and/or vedolizumab. At week 52, 45 (44%) patients had discontinued ustekinumab mainly due to lack of effectiveness (n = 41). The cumulative probabilities of ustekinumab persistence were 96.1%, 81.6%, 71.7% and 58.4% after 3, 6, 9 and 12 months respectively. The overall steroid-free clinical remission rate at week 52 was 32% of whom 71% had subscores of null for rectal bleeding and stool frequency. Ten patients underwent colectomy within a median of 6.7 [4.3-10.6] months. Adverse effects were observed in 15 (16.9%) patients; 4 (4.5%) were severe, including one patient who died from a myocardial infarction. CONCLUSION After 52 weeks, over one-half of patients with refractory UC were still treated by ustekinumab and one-third were in steroid-free clinical remission.
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Aguiar Zdovc J, Hanžel J, Kurent T, Sever N, Koželj M, Smrekar N, Novak G, Štabuc B, Dreesen E, Thomas D, Vovk T, Ostanek B, Drobne D, Grabnar I. Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model. Pharmaceutics 2021; 13:pharmaceutics13101587. [PMID: 34683880 PMCID: PMC8538292 DOI: 10.3390/pharmaceutics13101587] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/22/2022] Open
Abstract
Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.
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Affiliation(s)
- Jurij Aguiar Zdovc
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
| | - Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tina Kurent
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Nejc Sever
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Matic Koželj
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Nataša Smrekar
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Gregor Novak
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Borut Štabuc
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (E.D.); (D.T.)
- Department of Pharmacy, Uppsala University, 751 23 Uppsala, Sweden
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (E.D.); (D.T.)
| | - Tomaž Vovk
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
| | - Barbara Ostanek
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Iztok Grabnar
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
- Correspondence: ; Tel.: +386-1-4769-543
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Sipponen T, Af Björkesten CG, Hallinen T, Ilus T, Soini E, Eberl A, Heikura M, Kellokumpu M, Koskela R, Nielsen C, Nuutinen H, Heikkinen M, Suhonen UM, Tillonen J, Wennerström ECM, Borsi A, Koivunen MR. A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn's disease patients in Finland. Scand J Gastroenterol 2021; 56:661-670. [PMID: 33820465 DOI: 10.1080/00365521.2021.1906315] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
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.
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Affiliation(s)
- Taina Sipponen
- Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | | | - Tuire Ilus
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | | | - Anja Eberl
- Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko Heikura
- Department of Gastroenterology, North Karelia Central Hospital, Joensuu, Finland
| | - Mikko Kellokumpu
- Department of Internal Medicine, Lapland Central Hospital, Rovaniemi, Finland
| | - Ritva Koskela
- Department of Medicine, Division of Gastroenterology, Oulu University Hospital, Oulu, Finland
| | - Christian Nielsen
- Department of Internal Medicine, Vaasa Central Hospital, Vaasa, Finland
| | - Heikki Nuutinen
- Division of Gastroenterology, Department of Medicine, Turku University Hospital, Turku, Finland
| | - Markku Heikkinen
- Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Ulla-Maija Suhonen
- Department of Internal Medicine, Kainuu Central Hospital, Kajaani, Finland
| | - Jyrki Tillonen
- Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland
| | - E Christina M Wennerström
- Medical Affairs, Janssen Cilag AB, Solna, Sweden.,Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Andras Borsi
- Janssen Cilag Limited, EMEA HEMAR, High Wycombe, United Kingdom
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Chaparro M, Garre A, Iborra M, Sierra M, Barreiro-de Acosta M, Fernández-Clotet A, de Castro L, Boscá-Watts M, Casanova MJ, López-García A, Lorente R, Rodríguez C, Carbajo AY, Arroyo MT, Gutiérrez A, Hinojosa J, Martínez-Pérez T, Villoria A, Bermejo F, Busquets D, Camps B, Cañete F, Manceñido N, Monfort D, Navarro-Llavat M, Pérez-Calle JL, Ramos L, Rivero M, Angueira T, Camo P, Carpio D, García-de-la-Filia I, González-Muñoza C, Hernández L, Huguet JM, Morales VJ, Sicilia B, Vega P, Vera I, Zabana Y, Nos P, Suárez Álvarez P, Calviño-Suarez C, Ricart E, Hernández V, Mínguez M, Márquez L, Hervías Cruz D, Rubio Iturria S, Barrio J, Gargayo-Puyuelo C, Francés R, Hinojosa E, del Moral M, Calvet X, Algaba A, Aldeguer X, Guardiola J, Mañosa M, Pajares R, Piqueras M, García-Bosch O, Lopez Serrano P, Castro B, Lucendo AJ, Montoro M, Castro Ortiz E, Mesonero F, García-Planella E, Fuentes DA, Bort I, Delgado-Guillena P, Arias L, Iglesias A, Calvo M, Esteve M, Domènech E, Gisbert JP. Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry. J Crohns Colitis 2021; 15:1846-1851. [PMID: 33860795 PMCID: PMC8083263 DOI: 10.1093/ecco-jcc/jjab070] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. METHODS Patients 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. RESULTS A 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; 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; 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. CONCLUSIONS Ustekinumab is effective in both 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.
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Affiliation(s)
- María Chaparro
- Gastroenterology Departments of: Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid. Spain,CORRESPONDENCE: María Chaparro, M.D., Ph.D, Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Universitario de La Princesa, Diego de León, 62. 28006 Madrid, Spain, Tel.: 34-913093911; Fax: 34-915204013, e-mail:
| | - Ana Garre
- Gastroenterology Departments of: Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid. Spain
| | - Marisa Iborra
- Hospital Universitario y Politécnico La Fe and CIBERehd, Valencia, Spain
| | - Mónica Sierra
- Complejo Asistencial Universitario de León, León, Spain
| | | | | | - Luisa de Castro
- Xerencia Xestion Integrada de Vigo, SERGAS. Vigo. Research Group in Digestive Diseases, Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO. Spain
| | - Maia Boscá-Watts
- Hospital Clinico de Valencia. Universitat de València, Valencia, Spain
| | - María José Casanova
- Gastroenterology Departments of: Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid. Spain
| | - Alicia López-García
- Hospital del Mar and Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain
| | - Rufo Lorente
- Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | | | - Ana Y Carbajo
- Hospital Universitario Río Hortega. Gerencia Regional de Salud de Castilla y León (SACYL). Valladolid, Spain
| | | | - Ana Gutiérrez
- Hospital General Universitario de Alicante and CIBERehd, IIS ISABIAL Alicante, Spain
| | | | | | - Albert Villoria
- Hospital Parc Taulí, Sabadell. Depàrtament de Medicina. Universitat Autònoma de Barcelona and CIBERehd, Spain
| | - Fernando Bermejo
- Hospital Universitario Fuenlabrada and Instituto de Investigación Sanitaria del Hospital La Paz (IdiPAZ), Madrid, Spain
| | - David Busquets
- Hospital Universitario de Girona Dr. Josep Trueta, Girona, Spain
| | - Blau Camps
- Hospital Universitario de Bellvitge, Barcelona, Spain
| | - Fiorella Cañete
- Hospital Universitari Germans Trials i Pujol and CIBERehd, Badalona, Spain
| | | | | | | | | | - Laura Ramos
- Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Montserrat Rivero
- Hospital Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain
| | - Teresa Angueira
- Hospital General de Tomelloso and CIBERehd, Ciudad Real, Spain
| | | | - Daniel Carpio
- Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | | | | | | | - José M Huguet
- Hospital General Universitario de Valencia, Valencia, Spain
| | | | | | - Pablo Vega
- Complejo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Isabel Vera
- Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Yamile Zabana
- Hospital Universitario Mútua Terrassa and CIBERehd, Terrassa, Spain
| | - Pilar Nos
- Hospital Universitario y Politécnico La Fe and CIBERehd, Valencia, Spain
| | | | | | - Elena Ricart
- Hospital Clìnic i Provincial and CIBERehd, IDIBAPS, Barcelona, Spain
| | - Vicent Hernández
- Xerencia Xestion Integrada de Vigo, SERGAS. Vigo. Research Group in Digestive Diseases, Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO. Spain
| | - Miguel Mínguez
- Hospital Clinico de Valencia. Universitat de València, Valencia, Spain
| | - Lucía Márquez
- Hospital del Mar and Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain
| | | | | | - Jesús Barrio
- Hospital Universitario Río Hortega. Gerencia Regional de Salud de Castilla y León (SACYL). Valladolid, Spain
| | | | - Rubén Francés
- Hepatic and intestinal Immunobiology group Clinical Medicina, Department Miguel Hernández University, IIS ISABIAL, Hospital General Universitario de Alicante and CIBERehd, Alicante, Spain
| | | | | | - Xavier Calvet
- Hospital Parc Taulí, Sabadell. Depàrtament de Medicina. Universitat Autònoma de Barcelona and CIBERehd, Spain
| | - Alicia Algaba
- Hospital Universitario Fuenlabrada and Instituto de Investigación Sanitaria del Hospital La Paz (IdiPAZ), Madrid, Spain
| | - Xavier Aldeguer
- Hospital Universitario de Girona Dr. Josep Trueta, Girona, Spain
| | | | - Miriam Mañosa
- Hospital Universitari Germans Trials i Pujol and CIBERehd, Badalona, Spain
| | - Ramón Pajares
- Hospital Infanta Sofía, San Sebastián de los Reyes, Spain
| | | | | | | | - Beatriz Castro
- Hospital Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain
| | | | | | | | | | | | | | | | | | - Lara Arias
- Hospital Universitario de Burgos, Burgos, Spain
| | - Agueda Iglesias
- Complejo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Marta Calvo
- Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Maria Esteve
- Hospital Universitario Mútua Terrassa and CIBERehd, Terrassa, Spain
| | - Eugeni Domènech
- Hospital Universitari Germans Trials i Pujol and CIBERehd, Badalona, Spain
| | - Javier P Gisbert
- Gastroenterology Departments of: Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid. Spain
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Restellini S, Afif W. Update on TDM (Therapeutic Drug Monitoring) with Ustekinumab, Vedolizumab and Tofacitinib in Inflammatory Bowel Disease. J Clin Med 2021; 10:1242. [PMID: 33802816 PMCID: PMC8002563 DOI: 10.3390/jcm10061242] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
The goal of therapeutic drug monitoring (TDM) is to optimize anti-TNF (tumor necrosis factor) biologic treatment in patients with inflammatory bowel disease (IBD). Although commercial assays are readily available for both ustekinumab and vedolizumab, the use of TDM with these newer biologic medications is at its infancy. The clinical utility of TDM with non-anti-TNF mechanisms of action is not clear. This review summarizes the latest available data on the pharmacokinetics of newer biologic and oral small molecules and highlights the threshold concentrations that have been associated with improved outcomes in IBD patients.
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Affiliation(s)
- Sophie Restellini
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC H3G 1A4, Canada;
- Division of Gastroenterology and Hepatology, Geneva’s University Hospitals and University of Geneva, 1205 Geneva, Switzerland
| | - Waqqas Afif
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC H3G 1A4, Canada;
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Gutiérrez A, Rodríguez-Lago I. How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data. Front Med (Lausanne) 2021; 8:640813. [PMID: 33585530 PMCID: PMC7876229 DOI: 10.3389/fmed.2021.640813] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022] Open
Abstract
Ustekinumab is a fully human IgG1 monoclonal antibody that has been approved for the treatment of moderate to severe Crohn's disease, and more recently moderate to severe ulcerative colitis. It binds with high affinity to the p40 subunit of human interleukin-12 and 23. This mechanism of action prevents the bioactivity of both interleukins, thus precluding their interaction with the cell surface receptor protein. The pivotal clinical trials (UNITI-1, UNITI-2 and IM-UNITI) demonstrated its clinical efficacy and safety, in naïve patients and also in those previously exposed to immunosuppressants and/or biologics. There is now an extensive experience with its use worldwide, corroborating its favorable profile even in patients with refractory disease. However, the number of medical treatment options available in inflammatory bowel disease are still limited. Hence, we should prioritize the treatments that have a greater probability of response in an individual patient. Our aim was to review and summarize all the available literature regarding the potential predictors of response to ustekinumab that can increase the success rate with this therapy in clinical practice.
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Affiliation(s)
- Ana Gutiérrez
- Gastroenterology Department, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital General Universitario de Alicante, Alicante, Spain
| | - Iago Rodríguez-Lago
- Gastroenterology Department, Hospital de Galdakao, Biocruces Bizkaia Health Research Institute, Galdakao, Spain
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