1
|
Lundekvam JA, Høivik ML, Anisdahl K, Småstuen MC, Warren DJ, Bolstad N, Medhus AW. Tumour necrosis factor inhibitors in Ulcerative colitis: real-world data on Therapeutic drug monitoring and evaluation of current treatment targets (STRIDE II). Ann Med 2025; 57:2424447. [PMID: 39757985 PMCID: PMC11721610 DOI: 10.1080/07853890.2024.2424447] [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: 09/29/2023] [Revised: 12/31/2023] [Accepted: 08/31/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND The benefit of therapeutic drug monitoring (TDM) and implementation of recommendations from the Selection of Therapeutic Targets in Inflammatory Bowel Disease (IBD, STRIDE) are discussed in the IBD community. We report real-world data in ulcerative colitis patients receiving first-line tumour necrosis factor inhibitor (TNFi) treatment followed by TDM, and assess how implementation of the STRIDE II recommendations might affect clinical practice. METHODS Adult, biologically naïve UC patients starting TNFi between 2014 and 2021 at Oslo University Hospital were included in a medical chart review study, and data were collected at three and twelve months after the start of treatment. Target serum drug levels were defined as ≥7.5 mg/L for adalimumab and ≥5 mg/L for infliximab. RESULTS Of 141 included patients, 36% were in clinical and biochemical (combined) remission after twelve months. Among 102 treatment persistent patients, 54% were in combined remission after twelve months. Target drug level at three months was associated with clinical remission at twelve months (OR = 2.97, 95% CI [1.24-7.12]) and biochemical remission at twelve months (OR = 2.64, 95% CI [1.03-6.77]). In total, 56% of recorded dosage adjustments were related only to serum drug levels. CONCLUSIONS Combined remission rates at twelve months for treatment persistent patients suggest that 46% should have been considered for a change of treatment according to the STRIDE II recommendations. A majority of dosage adjustments were made proactively. Target drug level at three months was associated with remission at twelve months and supports the use of proactive TDM.
Collapse
Affiliation(s)
- Jonas Andre Lundekvam
- Department of Gastroenterology, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo
| | - Marte Lie Høivik
- Department of Gastroenterology, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo
| | - Karoline Anisdahl
- Department of Gastroenterology, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo
| | - Milada Cvancarova Småstuen
- Department of Gastroenterology, Oslo University Hospital
- Department of Public Health, Oslo Metropolitan University
| | - David J. Warren
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet
| | - Asle Wilhelm Medhus
- Department of Gastroenterology, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo
| |
Collapse
|
2
|
Li X, Song FL, He HF, Zeng SM, Feng ZC, Rong PF. Longitudinal computed tomography-based delta-radiomics of visceral adipose tissue predicts infliximab secondary loss of response in Crohn’s disease patients. World J Gastroenterol 2025; 31:105895. [DOI: 10.3748/wjg.v31.i21.105895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/05/2025] [Accepted: 05/21/2025] [Indexed: 06/06/2025] Open
Abstract
BACKGROUND Visceral adipose tissue (VAT) plays a role in the pathogenesis of Crohn's disease (CD) and is associated with treatment outcomes following infliximab (IFX) therapy. We developed and validated the first delta-radiomics model to quantify VAT heterogeneity as a predictive biomarker for IFX response in patients with CD.
AIM To develop a longitudinal computed tomography (CT)-based delta-radiomics model of VAT for predicting secondary loss of response (SLR) in patients with CD.
METHODS This retrospective study included 161 patients with CD who achieved clinical remission following IFX induction therapy between 2015 and 2023. All patients underwent CT enterography before IFX initiation and after completing induction therapy. VAT volume was delineated by two radiologists in consensus. Radiomics features were extracted from pre-treatment and post-induction CT images, and delta-radiomics features were calculated as follows: Delta features = Feature-post - Feature-pre. A radiomics model was constructed using logistic regression. Model performance was assessed using discrimination, calibration, and decision curve analyses.
RESULTS Nine significant delta-radiomics features were used to develop the delta-radiomics model, yielding an area under the receiver operating characteristic curve (AUC) of 0.816 (95%CI: 0.737-0.896) in the training cohort and 0.750 (95%CI: 0.605-0.895) in the validation cohort. Multivariable logistic regression identified platelet count, Montreal behavior classification, and the VAT/subcutaneous adipose tissue volume ratio prior to treatment as independent risk factors for SLR. The combined model integrating clinical predictors and delta-radiomics features achieved superior predictive performance, with an AUC of 0.853 (95%CI: 0.786-0.921) in the training cohort and 0.812 (95%CI: 0.677-0.948) in the validation cohort.
CONCLUSION We developed a predictive model based on longitudinal changes in VAT, demonstrating significant potential for identifying patients with CD at high risk of SLR to IFX therapy.
Collapse
Affiliation(s)
- Xi Li
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Fu-Long Song
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Hai-Feng He
- Department of Radiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Shu-Min Zeng
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Chao Feng
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
- Department of Radiology, Department of Medical Imaging, SJTU-Ruijin-UIH Institute for Medical Imaging Technology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Medical Imaging, Yueyang Central Hospital, Yueyang 414020, Hunan Province, China
| | - Peng-Fei Rong
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| |
Collapse
|
3
|
Nardone OM, Vuyyuru SK, Yuan Y, Hanzel J, Jairath V. Differentiating IL-23 Inhibitors in Crohn's Disease. Drugs 2025; 85:725-740. [PMID: 40323342 DOI: 10.1007/s40265-025-02183-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 05/24/2025]
Abstract
Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, plays a critical role in intestinal homeostasis and inflammation and is strongly implicated in the pathogenesis of inflammatory bowel disease (IBD). Therapies targeting the p19 subunit of IL-23 have recently expanded the therapeutic options for IBD demonstrating efficacy and safety for the treatment of moderate to severe Crohn's disease (CD). Thus, in this review, we provide an overview of agents targeting the IL-23 pathway in CD, highlighting similarities and differences of specific IL-23 inhibitors. Furthermore, we summarize key phase 3 trials and head-to-head trials, focusing on design features and interpretation. Finally, we discuss the positioning of selective IL-23 agents for CD treatment along with areas of unmet clinical needs. However, real-world data will offer additional comparative effectiveness information, data for disease subtypes, and insights into the long-term outcomes of IL-23 inhibition. Looking ahead, ongoing phase 3 studies testing p19-specific selective IL-23 inhibitors are expected to expand the therapeutic options for patients with complex phenotypes, including those with extraintestinal manifestations (EIMs), fistulas, and strictures. Advances in molecular and cellular characterization, including the development of predictive molecular biomarkers, may help guide clinical decision-making, enabling more personalized treatment approaches. Precision medicine studies may further enhance our understanding of the molecular biology of IL-23, shedding light on how these agents work in complex CD and clarify their potential complementary or synergistic effects with other therapies.
Collapse
Affiliation(s)
- Olga Maria Nardone
- Department of Public Health, Gastroenterology, University Federico II of Naples, Naples, Italy
| | - Sudheer K Vuyyuru
- Department of Medicine, Division of Gastroenterology, Western University, London, ON, Canada
| | - Yuhong Yuan
- Department of Medicine, Division of Gastroenterology, Western University, London, ON, Canada
- Lawson Health Research Institute, London Health Science Centre, London, ON, Canada
| | - Jurij Hanzel
- Department of Gastroenterology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia
| | - Vipul Jairath
- Department of Medicine, Division of Gastroenterology, Western University, London, ON, Canada.
- Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
- Departments of Medicine, Epidemiology and Biostatistics, Division of Gastroenterology, University of Western Ontario, London, ON, N6A 5B6, Canada.
| |
Collapse
|
4
|
Song JH, Hong SN, Kim MG, Kim M, Kim SK, Kim ER, Chang DK, Kim YH. Population Pharmacokinetic Model for the Use of Intravenous or Subcutaneous Infliximab in Patients with Inflammatory Bowel Disease: Real-World Data from a Prospective Cohort Study. Gut Liver 2025; 19:376-387. [PMID: 40254990 PMCID: PMC12070208 DOI: 10.5009/gnl240503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 04/22/2025] Open
Abstract
Background/Aims Infliximab treatment failure in patients with inflammatory bowel disease may result from sub-optimal infliximab trough level. An understanding of pharmacokinetics (PKs) is important to maintain an optimal trough level. PK studies of the switch to subcutaneous (SC) infliximab from intravenous (IV) infliximab using real-world data are lacking. We aimed to develop a population PK model of IV and SC infliximab to predict individual infliximab exposure during maintenance therapy. Methods We used data from prospectively collected data on IV and SC infliximab concentrations in patients with inflammatory bowel disease receiving maintenance treatment from February 2020 to December 2022 at Samsung Medical Center. Population PK analysis was conducted by using a two-compartment model with first-order absorption and first-order elimination. Goodness-of-fit plots and visual predictive check were used to evaluate the PK model. Results A total of 2,132 samples from 181 patients (149 Crohn's disease and 32 ulcerative colitis) were analyzed. We developed an infliximab population PK model using body mass index, albumin, C-reactive protein level, and the anti-drug antibody level and validated its predictive performance. Conclusions It may be possible to predict the infliximab trough level of both IV and SC infliximab in patients with inflammatory bowel disease during maintenance treatment by using our model in real-world practice.
Collapse
Affiliation(s)
- Joo Hye Song
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myeong Gyu Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - Minjung Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - Seong Kyung Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
5
|
Anjie SI, Gecse KB, Meloni CM, Vidal-Itriago A, Löwenberg M, D'Haens GR. Immunogenicity and Efficacy of Subcutaneous Infliximab Monotherapy vs Combination Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00409-4. [PMID: 40378993 DOI: 10.1016/j.cgh.2025.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND & AIMS Intravenous (IV) infliximab (IFX) combined with an immunomodulator (combination therapy) outperforms IV IFX monotherapy in terms of clinical, endoscopic, and immunogenicity outcomes in patients with inflammatory bowel disease (IBD). With the advent of subcutaneous (SC) IFX, which is associated with higher serum drug concentrations, it is essential to assess whether SC IFX monotherapy provides similar pharmacokinetic and clinical benefits as combination therapy. METHODS We conducted a systematic review and meta-analysis (until August 2024), of studies on patients with IBD treated with SC IFX. The primary outcome was anti-drug antibodies (ADAs) formation within 12 months (M) after starting SC IFX or after switching from IV to SC IFX. Secondary outcomes included treatment persistence, clinical efficacy, and biochemical parameters. RESULTS Twenty-four studies (n = 3172) were included. Among patients transitioning from IV IFX induction to SC IFX, immunogenicity was more prevalent with monotherapy than combination treatment (median, 68% vs 48%; odds ratio [OR], 3.29; 95% confidence interval [CI], 1.71-6.31; P < .001). Clinical response rates at 12M were comparable, with a trend favoring combination therapy (OR, 0.73; 95% CI, 0.50-1.06; P = .10). In patients switching from IV maintenance to SC IFX, relapse rates were low (median, 12% at 6M, 11% at week 50), with stable biochemical markers. Treatment persistence was high (93% at 6M, 92% at 12M). Among patients with quiescent disease at the time of switching, 1-year relapse rates were 9% to 11%, with baseline immunogenicity predicting treatment failure. CONCLUSION SC IFX monotherapy is associated with higher immunogenicity rates compared with combination therapy, particularly in new IFX starters. Although clinical response was comparable, a trend favoring combination therapy warrants further investigation.
Collapse
Affiliation(s)
- Suzanne I Anjie
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands.
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Chiara M Meloni
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | | | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| |
Collapse
|
6
|
Zhao M, Larsen L, Dige A, Poulsen A, Lo B, Attauabi M, Ovesen PD, Wewer MD, Christiansen D, Hvas CL, Petersen AM, Bendtsen F, Seidelin J, Burisch J. Clinical Outcomes After First-Line Anti- Tumor-Necrosis-Factor Treatment of Patients With Inflammatory Bowel Disease-A Prospective Multicenter Cohort Study. J Crohns Colitis 2025; 19:jjae192. [PMID: 39700468 DOI: 10.1093/ecco-jcc/jjae192] [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: 08/20/2024] [Revised: 12/05/2024] [Accepted: 12/18/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND AND AIMS Existing findings on outcomes of anti-tumor-necrosis-factor (TNF) therapy in patients with inflammatory bowel diseases (IBD) are largely based on retrospective studies. We aimed to investigate real-world outcomes of anti-TNF therapy and predictors thereof in a prospective IBD cohort. METHODS In a Danish multicenter cohort of adult bio-naïve patients with IBD treated with anti-TNF, we assessed clinical response and remission to induction therapy using clinical disease activity scoring indices at Week 14. In patients who continued treatment beyond the induction period, we also assessed loss of response (LOR), drug withdrawal, and major IBD surgery during maintenance therapy. RESULTS This study included 774 patients (706 infliximab, 68 adalimumab) followed for a median duration of 125 weeks Clinical response was achieved in 209/331 (67.4%) of ulcerative colitis (UC) and 125/197 (74.0%) of Crohn's disease (CD) patients, while 143/331 (46.1%) UC and 81/197 (47.9%) CD patients achieved clinical remission. In 294 UC and 309 CD patients received maintenance therapy, while 86/294 (29.3%) UC and 78/309 (25.2%) CD patients experienced LOR. Active smoking and less severe disease activity predicted favorable outcomes in UC, while short disease duration, colonic disease, nonstricturing behavior, and concomitant immunomodulator therapy predicted favorable outcomes in CD. CONCLUSIONS Clinical response was achieved in 2 in 3 UC and 3 in 4 CD patients, meanwhile, one-third of UC and one-fourth of CD patients experienced LOR despite the short disease duration in this study. Several clinical features were associated with outcomes and may be useful predictors of anti-TNF treatment response.
Collapse
Affiliation(s)
- Mirabella Zhao
- Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
| | - Lone Larsen
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University, Copenhagen, Denmark
| | - Anders Dige
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Anja Poulsen
- Digestive Disease Center, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Bobby Lo
- Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
| | - Mohamed Attauabi
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Pernille Dige Ovesen
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads Damsgaard Wewer
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Dagmar Christiansen
- Digestive Disease Center, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Christian Lodberg Hvas
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark
| | - Andreas Munk Petersen
- Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Microbiology, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Seidelin
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johan Burisch
- Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Gastrounit, Medical Section, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
7
|
Teichert C, Anjie SI, Stevens TW, Bahur B, Bray KR, Gecse KB, D'Haens GR. Clinical Utility and Accuracy of Point-of-Care Testing for Anti-TNF Drug Monitoring and Loss of Response. Inflamm Bowel Dis 2025:izaf101. [PMID: 40334112 DOI: 10.1093/ibd/izaf101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND AND AIMS Point-of-care tests (POCT) enable immediate measurement of anti-TNF blood concentrations. This study examined the association between loss of response (LOR) to infliximab (IFX) or adalimumab (ADL) and serum concentrations measured with POCT and enzyme-linked immunosorbent assay (ELISA) in inflammatory bowel disease (IBD) patients. METHODS Patients with IBD with stored IFX or ADL serum samples were recruited. POCT was conducted, agreement with ELISA was evaluated using Bland-Altman plots. The primary endpoint was LOR defined as change in therapy, IBD-related surgery, new actively draining fistula, and/or endoscopic deterioration. ROC curves and quartile analysis assessed the association between concentrations and LOR. RESULTS A total of 176 patients were included (92 IFX/84 ADL, 154 Crohn's disease, and 22 ulcerative colitis). Median follow-up time was 20 months (interquartile range 9-38). LOR occurred in 37/84 (44%) ADL users and 55/92 (60%) IFX users. Median serum concentrations were significantly lower in LOR patients compared with sustained response, measured by both techniques for ADL (POCT: 6.45 vs 13.48 µg/mL, P <.001; ELISA: 4.80 vs 8.80 µg/mL, P <.001) and IFX (POCT: 2.39 vs 6.50 µg/mL, P <.001; ELISA: 1.70 vs 4.40 µg/mL, P <.001). Quartile analysis revealed that higher serum concentrations were associated with maintained response. ROC curve analysis demonstrated good or excellent discrimination for POCT and ELISA in association with LOR (AUC IFX: POCT = 0.82, ELISA = 0.76; AUC ADL: POCT = 0.82, ELISA = 0.81; all P <.0001). An overestimation of serum concentrations with POCT was observed. CONCLUSIONS Serum ADL and IFX POCT concentrations are comparable to ELISA and associated with LOR, indicating its clinical utility.
Collapse
Affiliation(s)
- Christoph Teichert
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Suzanne I Anjie
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Toer W Stevens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Bayda Bahur
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA, USA
| | - Kurtis R Bray
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA, USA
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| |
Collapse
|
8
|
Temido MJ, Honap S, Jairath V, Vermeire S, Danese S, Portela F, Peyrin-Biroulet L. Overcoming the challenges of overtreating and undertreating inflammatory bowel disease. Lancet Gastroenterol Hepatol 2025; 10:462-474. [PMID: 39919770 DOI: 10.1016/s2468-1253(24)00355-8] [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: 06/07/2024] [Revised: 10/20/2024] [Accepted: 10/22/2024] [Indexed: 02/09/2025]
Abstract
Several therapeutic advances have been achieved over the past two decades for inflammatory bowel disease (IBD). The expanding therapeutic armamentarium and the increasingly ambitious treatment targets have led to an increased use of advanced therapies and better outcomes. Nevertheless, many patients remain suboptimally treated and are at risk of disease progression, hospital admission, and surgery, even when advanced therapies are cycled, escalated, or combined. Conversely, IBD can also be characterised by an indolent disease course. Top-down and treat-to-target strategies, although beneficial in a substantial proportion of patients, might not be advantageous in patients with mild disease and might risk overtreatment. Identifying patients with mild activity and a benign disease trajectory in the long-term is important; unnecessary exposure to advanced therapies increases the risk of adverse events and increases financial costs and health-care resource utilisation. This Review details the importance of adopting clinical strategies to avoid the pitfalls of undertreating and overtreating IBD.
Collapse
Affiliation(s)
- Maria José Temido
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France; Gastroenterology Department, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
| | - Sailish Honap
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France; Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK; School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine; Lawson Health Research Institute; and Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Severine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Francisco Portela
- Gastroenterology Department, Unidade Local de Saúde de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, Vandœuvre-lès-Nancy, France.
| |
Collapse
|
9
|
Kim SM, Oh H, Hong SN, Kim MJ, Choe YH, Lee SY. A Bottom-Up Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Infliximab: Method Development, Comparison With 2 Enzyme-Linked Immunosorbent Assay Methods, and Evaluation of Anti-Drug Antibody Interference. Arch Pathol Lab Med 2025; 149:448-456. [PMID: 39041105 DOI: 10.5858/arpa.2023-0573-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2024] [Indexed: 07/24/2024]
Abstract
CONTEXT.— Therapeutic drug monitoring is recommended to optimize infliximab use and improve outcome in chronic inflammatory disorders. OBJECTIVE.— To describe a simple and affordable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure infliximab in serum. DESIGN.— Infliximab was measured using winged stable isotope-labeled peptides as internal standards. Linearity, lower limit of measuring interval, limit of detection, precision, accuracy, carryover, and ion suppression were evaluated. Method comparison against 2 enzyme-linked immunosorbent assay (ELISA) methods (Remsima Monitor and IDKmonitor Infliximab) and anti-drug antibody (ADA) interference were evaluated using clinical specimens from inflammatory bowel disease patients (N = 237). RESULTS.— Analytical run time and sample preparation time were 5 minutes per sample and 3 hours per batch, respectively. Analytical measurement interval and limit of detection were 0.50 to 50.0 μg/mL (R2 = 0.998) and 0.25 μg/mL, respectively. The intraday and interday imprecision percentage coefficients of variation were less than 6.1%. Accuracy was 94.2% to 98.7%. No significant ion suppression or carryover was observed. Infliximab concentrations measured by LC-MS/MS showed good agreement with those measured by Remsima Monitor (mean percentage difference, 5.7%; 95% CI, -1.2% to 12.6%) but were markedly lower than those measured by IDKmonitor (-32.6%; -35.8% to -29.4%), demonstrating significant bias between ELISAs. Although a good agreement between LC-MS/MS and ELISA was observed for ADA-negative samples (-3.5%; -12.8% to 5.9%), a significant bias was observed for ADA-positive samples (13.6%; 1.7% to 25.6%). CONCLUSIONS.— This simple, fast, and affordable LC-MS/MS method for infliximab quantitation could improve standardization of infliximab quantitation and optimization of infliximab use in patients with high-titer ADA.
Collapse
Affiliation(s)
- Sang-Mi Kim
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- the Department of Laboratory Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju, Republic of Korea (S.-M. Kim)
| | - Hyeonju Oh
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Noh Hong
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mi Jin Kim
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yon Ho Choe
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soo-Youn Lee
- From the Departments of Laboratory Medicine and Genetics (S.-M. Kim, Oh, Lee), Internal Medicine (Hong), and Pediatrics (M. J. Kim, Choe), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| |
Collapse
|
10
|
Schreiber S, Colombel JF, Hanauer SB, Sandborn WJ, Danese S, Lee SJ, Kim SH, Bae YJ, Lee SH, Lee SG, Lee JH, Kim JM, Park GH, Lee J, Lee JH, Kim CY, Sands BE. Comparing Outcomes With Subcutaneous Infliximab (CT-P13 SC) by Baseline Immunosuppressant Use: A Post Hoc Analysis of the LIBERTY-CD and LIBERTY-UC Studies. Inflamm Bowel Dis 2025:izaf038. [PMID: 40300779 DOI: 10.1093/ibd/izaf038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Indexed: 05/01/2025]
Abstract
BACKGROUND Superior efficacy of subcutaneous infliximab (CT-P13 SC) over placebo for maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated in the randomized LIBERTY-CD and LIBERTY-UC studies. The current post hoc analysis compared outcomes with CT-P13 SC by baseline immunosuppressant use. METHODS Patients with moderately to severely active CD or UC randomized to the CT-P13 SC maintenance arm of the 54-week LIBERTY trials at week 10 and who were treated in the open-label extension (weeks 56-102) were included. Pharmacokinetic, efficacy, biomarker, safety, and immunogenicity endpoints were evaluated by baseline immunosuppressant use (monotherapy vs combination therapy). RESULTS A total of 192 patients with CD (monotherapy, n = 126; combination therapy, n = 66) and 237 patients with UC (monotherapy, n = 180; combination therapy, n = 57) were included. In both studies, efficacy outcomes were generally comparable between monotherapy and combination therapy at week 54 or week 102. Serum concentrations were generally higher, and antidrug antibody-positive conversion rates were lower, with combination therapy relative to monotherapy. In combined analyses of CD and UC, comparable safety profiles were observed between monotherapy and combination therapy. CONCLUSIONS Despite some differences in pharmacokinetics and immunogenicity between CT-P13 SC received alone or in combination with immunosuppressants in patients with CD or UC, efficacy outcomes at week 54 or week 102 were generally comparable. The overall safety profile and incidence of systemic injection reactions were also comparable between monotherapy and combination therapy.
Collapse
Affiliation(s)
- Stefan Schreiber
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jean-Frederic Colombel
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen B Hanauer
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Silvio Danese
- Department of Gastroenterology, IRCCS San Raffaele Hospital and Vita-Salute University, Milan, Italy
| | - Sang Joon Lee
- Data Science Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Sung Hyun Kim
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Yun Ju Bae
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Sun Hee Lee
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Seul Gi Lee
- Data Science Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Joon Ho Lee
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Jong Min Kim
- Data Science Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Ga Hee Park
- Data Science Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Jimin Lee
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Ju Hyun Lee
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Chae Young Kim
- Medical Science Division, Celltrion, Inc., Incheon, Republic of Korea
| | - Bruce E Sands
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
11
|
Stankey CT, Lee JC. The Role of ETS2 in Macrophage Inflammation. DNA Cell Biol 2025. [PMID: 40227609 DOI: 10.1089/dna.2025.0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Abstract
Autoimmune and inflammatory diseases are rising globally yet widely effective therapies remain elusive. Most treatments have limited efficacy, significant potential side effects, or eventually lose response, underscoring the urgent need for new therapeutic approaches. We recently discovered that ETS2, a transcription factor, functions as a master regulator of macrophage-driven inflammation-and is causally linked to the pathogenesis of multiple inflammatory diseases via human genetics. The pleotropic inflammatory effects of ETS2 included upregulation of many cytokines that are individually targeted by current disease therapies, including TNFα, IL-23, IL1β, and TNF-like ligand 1A signaling. With the move toward combination treatment-to maximize efficacy-targeting ETS2 presents a unique opportunity to potentially induce a broad therapeutic effect. However, there will be multiple challenges to overcome since direct ETS2 inhibition is unlikely to be feasible. Here, we discuss these challenges and other unanswered questions about the central role that ETS2 plays in macrophage inflammation.
Collapse
Affiliation(s)
- Christina T Stankey
- Genetic Mechanisms of Disease Lab, The Francis Crick Institute, London, United Kingdom
- Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
- Washington University School of Medicine, Saint Louis, Missouri, USA
| | - James Christopher Lee
- Genetic Mechanisms of Disease Lab, The Francis Crick Institute, London, United Kingdom
- Department of Gastroenterology, Royal Free Hospital, London, United Kingdom
- Division of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| |
Collapse
|
12
|
Doherty J, Ryan AW, Quinn E, Conroy J, Dolan J, Corcoran R, Hara FO, Cullen G, Sheridan J, Bailey Y, Dunne C, Hartery K, McNamara D, Doherty GA, Kevans D. HLA-DQA1*05 Allele Carriage and Anti-TNF Therapy Persistence in Inflammatory Bowel Disease. Inflamm Bowel Dis 2025; 31:903-911. [PMID: 38937958 DOI: 10.1093/ibd/izae138] [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: 01/12/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Carriage of the HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADAs) to antitumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease. However, ADA is not uniformly associated with treatment failure. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of biologic therapy evaluated by drug persistence. METHODS A multicenter, retrospective study of 877 patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy with HLA-DQA1*05 genotypes were generated by imputation from whole genome sequence using the HIBAG package, in R. Primary end point was anti-TNF therapy persistence, (time to therapy failure), segregated by HLA-DQA1*05 allele genotype and development of a risk score to predict anti-TNF therapy failure, incorporating HLA-DQA1*05 allele genotype status (LORisk score). RESULTS In all, 877 patients receiving anti-TNF therapy were included in our study; 543 (62%) had no copy, 281 (32%) one copy, and 53 (6%) 2 copies of HLA-DQA1*05 allele. Mean time to anti-TNF therapy failure in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared with patients with 0 or 1 copy at 700 days' follow-up: 418 vs 541 vs 513 days, respectively (P = .012). Factors independently associated with time to anti-TNF therapy failure included carriage of HLA-DQA1*05 allele (hazard ratio [HR], 1.2, P = .02; female gender HR, 1.6, P < .001; UC phenotype HR, 1.4, P = .009; and anti-TNF therapy type [infliximab], HR, 1.5, P = .002). The LORisk score was significantly associated with shorter time to anti-TNF therapy failure (P < .001). CONCLUSIONS Carriage of 2 HLA-DQA1*05 alleles is associated with less favorable outcomes for patients receiving anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in patients with IBD.
Collapse
Affiliation(s)
- Jayne Doherty
- Gastroenterology Department, St James's Hospital, Dublin, Ireland
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| | | | - Emma Quinn
- Genuity Science (Ireland) Limited, Dublin, Ireland
| | | | - Jackie Dolan
- Genuity Science (Ireland) Limited, Dublin, Ireland
| | - Roisin Corcoran
- Gastroenterology Department, St James's Hospital, Dublin, Ireland
- Trinity Academic Gastroenterology Group, School of Medicine, Trinity College Dublin, Ireland
| | - Fintan O Hara
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
| | - Garret Cullen
- Department of Gastroenterology, St Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| | - Juliette Sheridan
- Department of Gastroenterology, St Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| | - Yvonne Bailey
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
| | - Cara Dunne
- Gastroenterology Department, St James's Hospital, Dublin, Ireland
| | - Karen Hartery
- Gastroenterology Department, St James's Hospital, Dublin, Ireland
| | - Deirdre McNamara
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
- Trinity Academic Gastroenterology Group, School of Medicine, Trinity College Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| | - Glen A Doherty
- Department of Gastroenterology, St Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| | - David Kevans
- Gastroenterology Department, St James's Hospital, Dublin, Ireland
- Trinity Academic Gastroenterology Group, School of Medicine, Trinity College Dublin, Ireland
- Wellcome-HRB Clinical Research Facility, St James's Hospital, Dublin, Ireland
- INITIative IBD Research Network, Dublin, Ireland
| |
Collapse
|
13
|
Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
Collapse
Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| |
Collapse
|
14
|
Rueda García JL, Suárez-Ferrer C, Amiama Roig C, García Ramírez L, García Rojas C, Martín-Arranz E, Poza Cordón J, Sánchez Azofra M, Noci J, Cubillo García C, Martín-Arranz MD. Association of early therapeutic drug monitoring of adalimumab with biologic remission and drug survival in Crohn's Disease. Therap Adv Gastroenterol 2025; 18:17562848251324226. [PMID: 40110342 PMCID: PMC11921000 DOI: 10.1177/17562848251324226] [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: 12/10/2024] [Accepted: 02/12/2025] [Indexed: 03/22/2025] Open
Abstract
Background Therapeutic drug monitoring of adalimumab (ADA) is still controversial. Objectives To study the association between ADA trough levels in the early stages of treatment with biological remission (BR) and drug survival in Crohn's disease (CD). Design Retrospective cohort study. Methods Patients treated with ADA with available trough levels at weeks 2 and 6 (after the first induction and maintenance dose, respectively) were included. Fecal calprotectin (Fcal) and C-reactive protein (CRP) were registered at baseline, week 24, and week 52. BR was defined as Fcal <200 µg/g and CRP <5 mg/dl. Treatment survival and the need for dose escalation were assessed at week 52. Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic accuracy of ADA cutoff levels for BR. Quartile-specific comparisons were performed to evaluate differences in the proportion of patients achieving BR at weeks 24 and 52, drug survival, and dose escalation. Results In all, 112 patients were included. ADA trough levels at week 6 were higher in patients achieving BR at week 24 (12.32 μg/ml vs 10.3 μg/ml, p = 0.0008), week 52 (12.3 μg/ml vs 10.8 μg/ml, p = 0.035), and in patients with 1-year treatment persistence (12.17 μg/ml vs 9.7 μg/ml, p = 0.03), but lower in patients requiring maintenance intensification (9.7 μg/ml vs 12.2 µg/ml, p < 0.0001). ADA week 6 trough levels >12.27 μg/ml predicted BR at week 24 with 79.7% specificity and 79.5% positive predictive value. Patients in the third quartile (Q3) and fourth quartile (Q4) of ADA levels at week 6 exhibited higher rates of BR at week 24, BR at week 52, 1-year drug survival, and less need for dose escalation (all p-values <0.05). In logistic regression, Q3 and Q4 of week 6 levels were significantly associated with BR at week 24 (p = 0.02 and p = 0.001); and week 6 Q4 with BR at week 52 (p = 0.02), treatment persistence (p = 0.03), and lower dose escalation (p = 0.004). ADA trough levels at week 2 did not show similar associations. Conclusion ADA trough levels at week 6 are associated with BR at weeks 24 and 52, drug survival, and need for dose escalation in CD. However, ADA concentrations at week 2 failed to yield similar results.
Collapse
Affiliation(s)
- José Luis Rueda García
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Paseo de la Castellana 261, Madrid 28046, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Cristina Suárez-Ferrer
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Clara Amiama Roig
- Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Laura García Ramírez
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Cristina García Rojas
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Eduardo Martín-Arranz
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Joaquín Poza Cordón
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - María Sánchez Azofra
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Jesús Noci
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - Cristina Cubillo García
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
| | - María Dolores Martín-Arranz
- Inflammatory Bowel Disease Unit, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ Study Group for Immune-Mediated Gastrointestinal Diseases, La Paz Institute for Health Research (IdiPAZ)-IdiPAZ, Madrid, Spain
- School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| |
Collapse
|
15
|
Shubow S, Gunsior M, Rosenberg A, Wang YM, Altepeter T, Guinn D, Rajabiabhari M, Kotarek J, Mould DR, Zhou H, Cheifetz AS, Garces S, Chevalier R, Gavan S, Trusheim MR, Rispens T, Bray K, Partridge MA. Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and Opportunities - a Workshop Report. AAPS J 2025; 27:62. [PMID: 40087239 DOI: 10.1208/s12248-025-01050-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/23/2025] [Indexed: 03/17/2025] Open
Abstract
Therapeutic drug monitoring (TDM) for dose modification of biologics has the potential to improve patient outcomes. The US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS) hosted the first US-based public workshop on TDM of biologics with contributions from a broad array of interested parties including healthcare providers, clinical pharmacologists, test developers, bioanalysis and immunogenicity scientists, health economics and outcomes research (HEOR) experts and regulators. The key insight was that despite a body of evidence to support TDM in certain therapeutic areas, there remain substantial challenges to widespread clinical implementation. There is a lack of consensus regarding the integration of TDM in clinical guidelines, and a lack of consensus on the cost-effectiveness of TDM; both factors contribute to the difficulty that healthcare providers face in obtaining reimbursement for TDM (both coverage of testing itself, and coverage of potential dosing modifications). The HEOR experts outlined alternative routes to obtaining reimbursement and suggested advocating for changes in coverage policies to promote TDM use in the clinic. Reaching alignment across policy makers, patients and advocacy groups, payers, and healthcare providers, on specific treatment settings where TDM will be clearly beneficial, was identified as an important step to advancing TDM implementation for the benefit of patients.
Collapse
Affiliation(s)
- Sophie Shubow
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | | | | | - Yow-Ming Wang
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Tara Altepeter
- Division of Gastroenterology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Daphne Guinn
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | | | - Joseph Kotarek
- Office of Health Technology 7, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Diane R Mould
- Projections Research Inc., Phoenixville, Pennsylvania, USA
| | - Honghui Zhou
- Jazz pharmaceuticals, Philadelphia, Pennsylvania, USA
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Rachel Chevalier
- Children's Mercy Kansas City, University of Missouri-Kansas City (UMKC), Kansas City, USA
| | - Sean Gavan
- Manchester Centre for Health Economics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | | | - Theo Rispens
- Amsterdam institute for Immunology and Infectious diseases, Immunology, Amsterdam, Netherlands
| | | | | |
Collapse
|
16
|
Samanta A, Srivastava A. Biologics in the management of pediatric inflammatory bowel disease: When and what to choose. World J Clin Pediatr 2025; 14:100938. [PMID: 40059900 PMCID: PMC11686582 DOI: 10.5409/wjcp.v14.i1.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Pediatric inflammatory bowel disease (PIBD) is a chronic inflammatory disorder of the gastrointestinal tract, with rising global incidence and prevalence. Over the past two decades, biologics have added to the therapeutic armamentarium and revolutionized the approach to treatment of inflammatory bowel disease. The available biologics include monoclonal antibodies which target inflammatory cytokines (anti-tumor necrosis factor alpha, anti-interleukin 12/23) or recruitment of leucocytes to the gastrointestinal tract (anti-alpha4beta7 integrin) and small molecules (Janus kinase inhibitors, sphingosine 1-phosphate-inhibitors) which modify the proinflammatory signaling. Considering their potential disease-modifying ability, recent pediatric guidelines from the West have advocated upfront use of biologics in appropriate clinical scenarios as a top-down approach rather than the conventional step-up approach. Although real-world studies are available regarding the clinical efficacy of biologics in PIBD, there is paucity of long-term outcome and safety data in children. Also, little information is available about the best approach in the newly industrialized - developing countries where PIBD is rising but at the same time, infections are prevalent and resources are limited. In this review, we summarize the efficacy and safety profile of biologics and small molecule drugs and discuss the challenges in the management of PIBD, especially in the developing world, and future directions.
Collapse
Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| |
Collapse
|
17
|
Wang J, Guay H, Chang D. Crohn's Disease and Ulcerative Colitis Share 2 Molecular Subtypes With Different Mechanisms and Drug Responses. J Crohns Colitis 2025; 19:jjae152. [PMID: 39361323 DOI: 10.1093/ecco-jcc/jjae152] [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: 06/03/2024] [Revised: 09/04/2024] [Accepted: 10/02/2024] [Indexed: 03/29/2025]
Abstract
BACKGROUND AND AIMS Several therapies have been approved to treat Crohn's disease (CD) and ulcerative colitis (UC), indicating that both diseases may share the same molecular subtypes. The aim of this study is to identify shared patient subtypes with common molecular drivers of disease. METHODS Five public datasets with 406 CD and 421 UC samples were integrated to identify molecular subtypes. Then, the patient labels from 6 independent datasets and 8 treatment datasets were predicted for validating subtypes and identifying the relationship with response status of corticosteroids, infliximab, vedolizumab, and ustekinumab. RESULTS Two molecular subtypes were identified from the training datasets, in which CD and UC patients were relatively evenly represented in each subtype. We found 6 S1-specific gene modules related to innate/adaptive immune responses and tissue remodeling and 9 S1-specific cell types (cycling T cells, Tregs, CD8+ lamina propria, follicular B cells, cycling B cells, plasma cells, inflammatory monocytes, inflammatory fibroblasts, and postcapillary venules). Subtype S2 was associated with 3 modules related to metabolism functions and 4 cell types (immature enterocytes, transit amplifying cells, immature goblet cells, and WNT5B+ cells). The subtypes can be replicated in 6 independent datasets based on a 20-gene classifier. Furthermore, response rates to 4 treatments in subtype S2 were significantly higher than those in subtype S1. CONCLUSIONS This study discovered and validated a robust transcriptome-based molecular classification shared by CD and UC and built a 20-gene classifier. Because 2 subtypes have different molecular mechanisms and drug response, our classification may aid interpretation of heterogeneous molecular and clinical information in inflammatory bowel disease patients.
Collapse
Affiliation(s)
- Jing Wang
- Genomic Research Center, AbbVie Inc., Cambridge, MA, USA
| | - Heath Guay
- AbbVie Bioresearch Center, Worcester, MA, USA
| | - Dan Chang
- Genomic Research Center, AbbVie Inc., Cambridge, MA, USA
| |
Collapse
|
18
|
Durham K, Atagozli T, Elliott DE, Ince MN. Laboratory Tests in Inflammatory Bowel Disease: An Evidence-Based Approach to Daily Practice. Biomedicines 2025; 13:491. [PMID: 40002904 PMCID: PMC11852734 DOI: 10.3390/biomedicines13020491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/25/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Inflammatory bowel diseases (IBDs) comprise a group of chronic gastrointestinal disorders characterized by periods of relapse and remission. The mainstay of treatment is medical, involving medications such as steroids, immune modulators, monoclonal antibodies (categorized as biologics), and small molecules. These medications can provide profound therapeutic benefits, but they can also cause severe and irreversible toxicities. Clinicians may utilize laboratory tests in the diagnosis and management of IBD including assessment of disease activity, monitoring medication response or toxicity, surveillance of infectious complications, and detection of nutritional deficiencies. Routine use of laboratory tests may help clinicians avoid reactivation of life-threatening infections such as tuberculosis or hepatitis B virus upon initiation of immune suppressive therapy. They can also be used to detect vitamin deficiencies such as B12 deficiency, which has the potential to cause irreversible neurologic damage. While some laboratory tests constitute established practices, the utility of newer tests such therapeutic drug monitoring (TDM) in the era of biologics is an evolving topic. Although clinical assessment with imaging, endoscopic, and histopathological examination is standard practice, laboratory tests serve as valuable adjuncts. We aim to explore the broad range of laboratory tests available to clinicians and to summarize their application in the current management of IBD in daily clinical practice, with special attention to updates in therapeutic drug monitoring.
Collapse
Affiliation(s)
- Katelin Durham
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA; (K.D.); (D.E.E.)
- Iowa City Veterans Affairs Medical Center, 601 Highway 6 W, Iowa City, IA 52246, USA
| | - Tyler Atagozli
- Carver College of Medicine, University of Iowa, 375 Newton Road, Iowa City, IA 52242, USA;
| | - David E. Elliott
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA; (K.D.); (D.E.E.)
- Iowa City Veterans Affairs Medical Center, 601 Highway 6 W, Iowa City, IA 52246, USA
| | - M. Nedim Ince
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA; (K.D.); (D.E.E.)
- Iowa City Veterans Affairs Medical Center, 601 Highway 6 W, Iowa City, IA 52246, USA
| |
Collapse
|
19
|
Atay A, Cagir Y, Ergul M, Ozturk O, Durak MB, Yuksel I. Comparative Outcomes of Adalimumab and Infliximab Dose Escalation in Inflammatory Bowel Disease Patients Failing First-Line Biologic Treatment. J Clin Med 2025; 14:1228. [PMID: 40004757 PMCID: PMC11857063 DOI: 10.3390/jcm14041228] [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: 01/07/2025] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Dose escalation has been commonly used to achieve and maintain response. We aimed to compare the outcomes of adalimumab or infliximab dose escalation in inflammatory bowel disease (IBD) patients. Methods: Treatment persistence (TP) and predictive factors for remission-free treatment discontinuation (r-fTD) were evaluated in patients treated with adalimumab or infliximab dose escalation between 2019 and 2024. Results: Dose escalation was identified in 142 patients treated with adalimumab (UC: 23.9%; CD: 76.1%) and in 126 patients treated with infliximab (UC: 23.8%; CD: 76.2%). The TP rate was significantly lower in the adalimumab group (35.2%) than the infliximab group (53.2%) (p = 0.003). The survival analysis showed that drug persistence was lower in the adalimumab group compared with the infliximab group (mean time: 74.3 vs. 99.5 months, p < 0.001). TP rates showed no significant differences between UC and CD for both adalimumab (mean time UC: 64.7 months vs. CD: 76.2 months, p = 0.403) and infliximab (mean time UC: 80.3 months and CD: 102.6 months, p = 0.151). The r-fTD rates were significantly higher in the adalimumab group (62.7%) than the infliximab group (39.7%) (p < 0.001). Primary lack of response and secondary loss of response (sLOR) rates were both higher in the adalimumab group (7.7% and 51.4%) than the infliximab group (1.6% and 28.6%). However, serious adverse events were lower in the adalimumab group (2.1%) than the infliximab group (7.9%) (p = 0.027). Conclusions: Infliximab dose escalation was more effective than adalimumab in both UC and CD patients. Regarding the side effect profile, adalimumab dose escalation was found to be safer compared with infliximab.
Collapse
Affiliation(s)
- Ali Atay
- Department of Gastroenterology, Ankara Bilkent City Hospital, 06800 Ankara, Turkey; (M.E.); (O.O.); (I.Y.)
| | - Yavuz Cagir
- Department of Gastroenterology, Ankara Yildirim Beyazit University Yenimahalle Training and Research Hospital, 06370 Ankara, Turkey;
| | - Mucahit Ergul
- Department of Gastroenterology, Ankara Bilkent City Hospital, 06800 Ankara, Turkey; (M.E.); (O.O.); (I.Y.)
| | - Oguz Ozturk
- Department of Gastroenterology, Ankara Bilkent City Hospital, 06800 Ankara, Turkey; (M.E.); (O.O.); (I.Y.)
| | - Muhammed Bahaddin Durak
- Department of Gastroenterology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey;
| | - Ilhami Yuksel
- Department of Gastroenterology, Ankara Bilkent City Hospital, 06800 Ankara, Turkey; (M.E.); (O.O.); (I.Y.)
- Department of Gastroenterology, School of Medicine, Ankara Yildirim Beyazit University, 06800 Ankara, Turkey
| |
Collapse
|
20
|
Shehab M, Alrashed F. Age as a Predictor of Serum Tumor Necrosis Factor Antagonist Drug and Antidrug Antibody Concentrations in Inflammatory Bowel Disease-A Nationwide Cohort Study. J Clin Med 2025; 14:1057. [PMID: 40004589 PMCID: PMC11856510 DOI: 10.3390/jcm14041057] [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: 01/10/2025] [Revised: 01/29/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Tumor necrosis factor antagonists (anti-TNFs) have been shown to be an effective treatment for inflammatory bowel disease (IBD). Several factors are associated with anti-TNF treatment failure. This study aims to explore the impact of age on serum concentrations of anti-TNF drugs and antidrug antibodies (ADAbs). Methods: We retrospectively reviewed patients' charts from July 2018 until September 2024 across seven medical centers. Patients with an established diagnosis of IBD receiving infliximab or adalimumab were included. The primary outcome of this study was the effect of age on the anti-TNFs serum drug concentration and ADAb levels. Linear regression was performed to explore the relationship between age and serum anti-TNF drug and ADAb levels. Results: 1093 patients were included in our cohort. In patients receiving infliximab, there was a significant association between older age and increasing ADAbs levels (p = 0.036), whereas in patients treated with adalimumab, there was no significant relationship between older age and ADAb levels (p = 0.771). There was no significant relationship between age and adalimumab serum concentration (p = 0.54). When stratified by age, patients taking infliximab who were >30 years of age developed more ADAbs compared to those aged ≤30 (p = 0.003). Conclusions: Patients older than 30 years of age receiving infliximab monotherapy have higher ADAbs and lower serum drug concentrations than younger patients. There was no statistically significant difference in ADAbs and serum drug concentrations among patients receiving infliximab combination therapy or adalimumab monotherapy.
Collapse
Affiliation(s)
- Mohammad Shehab
- Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Aljabreyah 47060, Kuwait;
- Department of Translational Medicine, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fatema Alrashed
- Department of Pharmacy Practice, College of Pharmacy, Kuwait University, Aljabreyah 13110, Kuwait
| |
Collapse
|
21
|
Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
Collapse
Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
| |
Collapse
|
22
|
Chen HC, Shunyakova J, Reddy AK, Pandiri S, Hassman L. Therapeutic drug monitoring and neutralizing anti-drug antibody detection to optimize TNF-alpha inhibitor treatment for uveitis. FRONTIERS IN OPHTHALMOLOGY 2025; 5:1432935. [PMID: 39936006 PMCID: PMC11810949 DOI: 10.3389/fopht.2025.1432935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 01/10/2025] [Indexed: 02/13/2025]
Abstract
Background Adalimumab taken every other week is an effective treatment in patients with chronic refractory uveitis. Patients who have a suboptimal response to this treatment may suffer from recurrent inflammation and vision loss. Here, we investigated the use of therapeutic drug monitoring and neutralizing anti-drug antibody detection as a strategy to optimize tumor necrosis factor (TNF)-alpha inhibitor treatment in patients who have a suboptimal response to the initial dosing of adalimumab. Method Retrospective cohort study performed in two tertiary referral uveitis services in the United States between 2015 to 2023. Patients with non-infectious uveitis who had a suboptimal response to every two-week dosing of adalimumab and underwent serum adalimumab level with reflex to anti-drug antibody testing were followed. Patients were considered to have neutralizing drug antibodies when serum drug levels were low (less than or equal to 6 mcg/mL) and anti-adalimumab antibodies were present on reflex testing. Treatment adjustment was made by clinicians with the knowledge of serum adalimumab level and the presence or absence of neutralizing drug antibodies. Every two-week dosing of adalimumab was either escalated to weekly dosing or switched to infliximab, an alternate TNF-alpha inhibitor, based on these findings. The primary outcome was success or failure at 12 months, as determined by disease inactivity on steroid-sparing therapy. Results 32 patients with suboptimal response to the initial dosing of adalimumab were included. 31.2% (n=10) of patients were found to have neutralizing drug antibodies. All patients with neutralizing drug antibodies underwent a medication switch to infliximab with a remission rate of 40% at 12 months. Patients without neutralizing drug antibodies (n=22) underwent dose escalation (77.3%; n=17) or medication switch (22.7%; n=5) and achieved a remission rate of 68.2% at 12 months. Altogether, treatment adjustment based on therapeutic drug monitoring and neutralizing drug antibody detection, in our cohort, resulted in a remission rate of 62.5%. Conclusions For patients with uveitis experiencing suboptimal therapeutic response to adalimumab dosed every two weeks, therapeutic drug monitoring and neutralizing drug antibody detection may help clinicians optimize TNF-alpha inhibitor treatment.
Collapse
Affiliation(s)
- Howard C. Chen
- John F. Hardesty Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
| | - Jenny Shunyakova
- Department of Ophthalmology, University of Kansas City School of Medicine, Kansas City, MO, United States
| | - Amit K. Reddy
- Department of Ophthalmology, University of Colorado, Aurora, CO, United States
| | - Srujay Pandiri
- Department of Ophthalmology, University of Kansas City School of Medicine, Kansas City, MO, United States
| | - Lynn Hassman
- Department of Ophthalmology, University of Colorado, Aurora, CO, United States
| |
Collapse
|
23
|
Reppell M, Zheng X, Dreher I, Blaes J, Regan E, Haslberger T, Guay H, Pivorunas V, Smaoui N. HLA-DQA1*05 Associates With Anti-Tumor Necrosis Factor Immunogenicity and Low Adalimumab Trough Concentrations in Inflammatory Bowel Disease Patients From the SERENE Ulcerative Colitis and Crohn's Disease Studies. J Crohns Colitis 2025; 19:jjae129. [PMID: 39162746 PMCID: PMC11725519 DOI: 10.1093/ecco-jcc/jjae129] [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: 05/28/2024] [Revised: 07/17/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND AND AIMS Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients. METHODS We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations. RESULTS This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05). CONCLUSIONS We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity. CLINICAL TRIAL REGISTRATION NUMBERS SERENE CD (NCT02065570), SERENE UC (NCT02065622).
Collapse
Affiliation(s)
| | | | | | - Jonas Blaes
- AbbVie Deutschland GmbH & Co, KG, Ludwigshafen, Germany
| | | | | | | | | | | |
Collapse
|
24
|
Mansouri P, Mansouri P, Behmard E, Najafipour S, Kouhpayeh A, Farjadfar A. Novel targets for mucosal healing in inflammatory bowel disease therapy. Int Immunopharmacol 2025; 144:113544. [PMID: 39571265 DOI: 10.1016/j.intimp.2024.113544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 10/13/2024] [Accepted: 10/28/2024] [Indexed: 12/15/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic condition affecting the gastrointestinal tract, primarily manifesting as ulcerative colitis (UC) or Crohn's disease (CD). Both inflammation and disruption of the intestinal epithelial barrier are key factors in IBD pathogenesis. Substantial evidence has revealed a significant association between aberrant immune responses and impairment of the intestinal epithelial barrier in IBD pathogenesis. The components of the intestinal epithelium, particularly goblet cells and Paneth cells, are crucial to gut homeostasis, as they secrete mucin, antimicrobial peptides (AMPs), and cytokines. Furthermore, impairment of epithelial integrity, which is regulated by tight junctions, is a hallmark of IBD pathology. While common treatments for IBD, such as anti-inflammatory drugs, target various signaling pathways with varying efficacies, therapeutic approaches focused on mucosal and epithelial barrier healing have been largely neglected. Moreover, high costs, side effects, and insufficient or inconsistent therapeutic outcomes remain major drawbacks of conventional anti-IBD drugs. Recent studies on epithelial barrier regeneration and permeability reduction have introduced promising therapeutic targets, including farnesoid X receptor (FXR), urokinase-type plasminogen activator (uPA)-urokinase-type plasminogen activator receptor (uPAR) interaction, fecal microbiota transplantation (FMT), and insulin receptor (INSR). Notably, the simultaneous targeting of intestinal inflammation and promotion of epithelial barrier healing shows promise for efficient IBD treatment. Future research should explore targeted therapies and combination treatments, including natural remedies, microbiota colonization, stem cell approaches, and computer-aided drug design. It is also crucial to focus on accurate prognosis and developing a thorough understanding of IBD development mechanisms.
Collapse
Affiliation(s)
- Pardis Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Pegah Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Esmaeil Behmard
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Sohrab Najafipour
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Amin Kouhpayeh
- Department of Pharmacology, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
| | - Akbar Farjadfar
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
| |
Collapse
|
25
|
Xiao P, Chen Z, Cai X, Xia W, Liu X, Song Z, Wang H, Zhao Y, Huang Y, Zhang Y, Guo K, Chen H, Liu R, Meng C, Fang Y, Lu Y, Cao Q. Targeting hyaluronan synthesis enhances the therapeutic effectiveness of biologics in inflammatory bowel disease. JCI Insight 2025; 10:e180425. [PMID: 39782690 PMCID: PMC11721290 DOI: 10.1172/jci.insight.180425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/13/2024] [Indexed: 01/12/2025] Open
Abstract
Although biologics have been revolutionizing the treatment of inflammatory bowel diseases (IBD) over the past decade, a significant number of patients still fail to benefit from these drugs. Overcoming the nonresponse to biologics is one of the top challenges in IBD treatment. In this study, we revealed that hyaluronan (HA), an extracellular matrix (ECM) component in the gut, is associated with nonresponsiveness to infliximab and vedolizumab therapy in patients with IBD. In murine colitis models, inhibition of HA synthase 2-mediated (HAS2-mediated) HA synthesis sensitized the therapeutic response to infliximab. Mechanistically, HA induced the expression of MMP3 in colonic fibroblasts by activating STAT3 signaling, thereby mediating the proteolytic cleavage of multiple IgG1 biologics. Finally, we found that macrophage-derived factors upregulated HAS2 expression in fibroblasts, thereby contributing to infliximab nonresponse. In summary, we identified a pathogenic connection between abnormal ECM remodeling and biologics nonresponse and provided insights for the precise therapy for IBD.
Collapse
Affiliation(s)
- Peng Xiao
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China
| | - Zhehang Chen
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Xuechun Cai
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Wenhao Xia
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Xia Liu
- ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China
| | | | | | - Yuening Zhao
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Youling Huang
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Yu Zhang
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Ke Guo
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Haotian Chen
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Rongbei Liu
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Changcheng Meng
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Yanfei Fang
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| | - Yunkun Lu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Cao
- Department of Gastroenterology and
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and
| |
Collapse
|
26
|
Petrov J, Fine S, Alzahrani R, Mohamed G, Al-Bawardy B. Ustekinumab Drug Levels and Outcomes in Inflammatory Bowel Disease. J Clin Gastroenterol 2025; 59:77-81. [PMID: 38300529 DOI: 10.1097/mcg.0000000000001978] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 01/07/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Data regarding the utility of therapeutic drug monitoring with ustekinumab (UST) are sparse. Our aim was to determine the correlation of UST levels with outcomes in a cohort of patients with inflammatory bowel disease (IBD). METHODS This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. The primary outcomes were the correlation of UST level with clinical remission (per physician global assessment), endoscopic healing [the absence of ulcers/erosions in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC)], and normal serum C-reactive protein (CRP) (≤5 mg/L). Secondary outcomes included defining optimal UST trough levels associated with favorable outcomes. RESULTS A total of 71 patients (74.6% with CD; 57.7% female) were included. The median age was 39.5 years [interquartile range (IQR): 26 to 52] and 12.6% were on combination therapy with immunomodulators. Median UST trough levels were significantly higher in patients who achieved endoscopic healing at 5.4 µg/mL versus 3.5 µg/mL ( P =0.035) and normal CRP at 5.5 µg/mL versus. 3.1 µg/mL ( P =0.002). A cutoff UST level of 4.8 µg/mL yielded the highest area under the curve (AUC) of 0.73 (95% CI: 0.61-0.80) to predict a normal CRP followed by a cutoff of 3.5 µg/mL which yielded an AUC of 0.66 (95% CI: 0.52-0.81) to predict endoscopic healing. CONCLUSIONS UST trough levels were significantly higher in patients who achieved a normal CRP and endoscopic healing. A cutoff UST level of 4.8 µg/mL reliably predicted CRP normalization.
Collapse
Affiliation(s)
- Jessica Petrov
- Department of Internal Medicine, Yale School of Medicine
| | - Sean Fine
- Department of Medicine, Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, RI
| | - Raneem Alzahrani
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital
| | - Gamal Mohamed
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital
| | - Badr Al-Bawardy
- Department of Internal 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, Riyadh, Saudi Arabia
| |
Collapse
|
27
|
Nielsen OH, Hammerhøj A, Ainsworth MA, Gubatan J, D'Haens G. Immunogenicity of Therapeutic Antibodies Used for Inflammatory Bowel Disease: Treatment and Clinical Considerations. Drugs 2025; 85:67-85. [PMID: 39532820 DOI: 10.1007/s40265-024-02115-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2024] [Indexed: 11/16/2024]
Abstract
The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.
Collapse
Affiliation(s)
- Ole Haagen Nielsen
- Department of Gastroenterology D112, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Copenhagen, Denmark.
| | - Alexander Hammerhøj
- Department of Gastroenterology D112, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Copenhagen, Denmark
| | - Mark Andrew Ainsworth
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - John Gubatan
- Department of Gastroenterology & Hepatology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Geert D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
28
|
Bourgonje AR, Dubinsky MC, Keizer RJ, Dreesen E, Mian P. Model-informed precision dosing in inflammatory bowel diseases. Trends Pharmacol Sci 2025; 46:9-19. [PMID: 39632196 DOI: 10.1016/j.tips.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/24/2024] [Accepted: 11/08/2024] [Indexed: 12/07/2024]
Abstract
Therapeutic drug monitoring (TDM) for biologic therapies in inflammatory bowel disease (IBD) primarily aims to optimize dosing. However, several unmet needs remain. These include the identification of optimal drug concentrations, accounting for variability in pharmacokinetics (PK) and pharmacodynamics (PD), and the frequent delays between sampling and clinical decision-making. Recent technical advances, such as population PK/PD modeling and model-informed precision dosing (MIPD) tools developed from such models, as well as point-of-care (POC) and self-sampling assays and novel software programs, offer potential solutions. Successful implementation of these innovations may help to establish MIPD for patients with IBD. This would enable personalized dosing, advancing a one-size-fits-all approach to TDM that currently is inadequate to fulfill the needs for every patient with IBD.
Collapse
Affiliation(s)
- Arno R Bourgonje
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Marla C Dubinsky
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Erwin Dreesen
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Paola Mian
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
29
|
Kumar NN, Ahmad Dit Al Hakim S, Grygiel-Górniak B. Antinuclear Antibodies in Non-Rheumatic Diseases. Arch Immunol Ther Exp (Warsz) 2025; 73:aite-2025-0004. [PMID: 39827475 DOI: 10.2478/aite-2025-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/04/2024] [Indexed: 01/22/2025]
Abstract
Antinuclear antibodies (ANAs) are critical immunological markers commonly associated with various connective tissue diseases (CTDs). However, these autoantibodies are also detectable in healthy individuals, patients with non-rheumatic autoimmune diseases, those with viral infections, and subjects using specific medications (such as procainamide, hydralazine, and minocycline) that can lead to drug-induced ANA elevation. The standard method for ANA detection is indirect immunofluorescence, a process that requires precision and thoroughness as it assesses both titer and fluorescence patterns. Additionally, immunoblotting and enzyme-linked immunosorbent assay (ELISA) are recommended to identify specific ANAs precisely, highlighting the importance of precision in ANA detection. This review explores the advantages and limitations of current ANA detection methods. It also describes the clinical implications of ANA presence in non-rheumatic diseases, including autoimmune disorders, infectious conditions, non-autoimmune and non-infectious diseases, and autoimmune cutaneous diseases. The presence of elevated ANA titers in these contexts can complicate clinical decision-making, as the diagnostic value of ANA testing alone is limited in non-rheumatic conditions. However, despite these limitations, ANA remains a key component in diagnosing and prognosis systemic CTDs, as it can indicate disease activity, severity, and response to treatment, which is of utmost importance in rheumatology and internal medicine. This paper provides a comprehensive review of the role of ANA in non-rheumatic diseases. It focuses on ANA diagnostic and prognostic significance and offers valuable insights for clinical practice.
Collapse
Affiliation(s)
- Nikita Niranjan Kumar
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Samir Ahmad Dit Al Hakim
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Bogna Grygiel-Górniak
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| |
Collapse
|
30
|
Genaro LM, Carron J, de Castro MM, Franceschini APMDF, Lourenço GJ, da Cruz CKNV, Reis GFSR, Pascoal LB, Mello JDC, Pereira IM, Nascimento ML, Oliveira PDSP, Corona LP, Ayrizono MDLS, Lima CSP, Leal RF. Therapeutic drug monitoring and immunogenetic factors associated with the use of adalimumab in Crohn's disease patients. Int J Immunopathol Pharmacol 2025; 39:3946320251319379. [PMID: 39959979 PMCID: PMC11831650 DOI: 10.1177/03946320251319379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/24/2025] [Indexed: 02/20/2025] Open
Abstract
Crohn's disease (CD) involves immune system interactions with intestinal tissue, driven by pro-inflammatory cytokines like Tumor Necrosis Factor (TNF-α). Adalimumab, targeting TNF-α, regulates associated inflammatory responses. Despite being humanized, it may induce immunogenic processes, affecting treatment effectiveness. Thus, monitoring serum adalimumab and anti-drug antibody (ADA) levels can optimize therapy. Understanding genetic factors influencing adalimumab response can enhance personalized treatment and improve patient quality of life. We aimed to quantify adalimumab serum levels, assess test interchangeability, detect ADA, examine immune complex formation, and investigate genetic phenotypes related to immunogenicity in CD patients. Seventy CD patients in the maintenance phase with adalimumab were classified into active (CDA) and remission (CDR) groups. Adalimumab concentration was determined via enzyme-linked immunosorbent assay (ELISA-Promonitor) and lateral flow assay (Quantum Blue), with assay interchangeability assessed statistically. ADA and immune complex formation were quantified using ELISA assays. DNA was genotyped for the genes ATG16L1, CD96, and CD155. No significant differences in adalimumab serum concentrations were observed between groups, regardless of the assay. However, a statistical difference between the tests indicated measurement disparity (P = 0.003), with moderate agreement (Lin's correlation of 0.247). ADA was detected in 4 of 27 of the patients with infratherapeutic levels, 3 in the CDA group and 1 in the CDR group. Analysis of immune complexes revealed significantly higher concentrations in the CDA group (P = 0.0125). The genotypic evaluation revealed significant associations for the CD96 CC (wild-type) genotype with higher CRP levels, colonic involvement, and infratherapeutic levels of adalimumab. ATG16L1 CC genotype was associated with higher CDEIS and fecal calprotectin values, while the variant (TT) genotype had lower platelet counts. The effectiveness of treatment with adalimumab was not directly related to higher medication levels in this cohort. The disparity between tests indicates the need to use only one test in patient follow-up to ensure accuracy in therapeutic monitoring. Genotypic differences highlight the correlation between the wild genotype for CD96 and ATG16L1 with unfavorable laboratory and endoscopic response to adalimumab. Finally, the more significant levels of immune complexes in the CDA group indicate an association with a worse response to adalimumab.
Collapse
Affiliation(s)
- Livia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Carron
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marina Moreira de Castro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ana Paula Menezes de Freitas Franceschini
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | | | | | - Livia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Delgado Campos Mello
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isabela Machado Pereira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Millene Leal Nascimento
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Priscilla De Sene Portel Oliveira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ligiana Pires Corona
- Nutritional Epidemiology Laboratory, School of Applied Sciences, University of Campinas (Unicamp), Limeira, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Carmen Silvia Passos Lima
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| |
Collapse
|
31
|
Chen Y, Wang F, Xu L, Ke Q, Ji S, Mao J, Jia X, Lai C, Dai S. Atypical Presentation of Small Bowel Crohn's Disease: Case Report of Musculoskeletal and Hepatic Complications Without Gastrointestinal Symptoms. J Inflamm Res 2024; 17:11129-11135. [PMID: 39713720 PMCID: PMC11660654 DOI: 10.2147/jir.s500687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024] Open
Abstract
Herein, we described a case of small bowel Crohn's disease with recurrent, unexplained fevers, pain in the right lower back, hip, and groin area over 20 months. The patient did not present any gastrointestinal symptoms and colonoscopy showed no abnormalities. Imaging revealed a liver abscess and multiple lesions with pneumatosis in the muscles of the right lower back region. Initially, disseminated infection was suspected and the antibiotics was administered without success. Subsequently, Magnetic resonance (MR) enterography suggested the possibility of a small bowel fistula which was confirmed during exploratory laparotomy. Inflammation was prominent in a 27-cm segment starting from 30-cm proximal to the ileocecal junction. The segment was resected and pathological examination confirmed Crohn's disease. Postoperatively, mesalazine was administered, but showed limited efficacy. After modifying the treatment plan to infliximab and azathioprine, the patient was symptom-free and no obvious inflammation was found in the colonoscopy reexamination.
Collapse
Affiliation(s)
- Yiyi Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Fei Wang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Lingna Xu
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Qinbing Ke
- Department of Radiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Shujuan Ji
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Jie Mao
- Department of Pathology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Xiya Jia
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Chuanxi Lai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| | - Sheng Dai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
- Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, People’s Republic of China
| |
Collapse
|
32
|
Clemente Bautista S, Segarra Cantón Ó, Padullés-Zamora N, García García S, Álvarez Beltrán M, Larrosa García M, Cabañas Poy MJ, Sanz-Martínez MT, Vázquez A, Gorgas Torner MQ, Miarons M. Long-Term Effectiveness and Safety of Proactive Therapeutic Drug Monitoring of Infliximab in Paediatric Inflammatory Bowel Disease: A Real-World Study. Pharmaceutics 2024; 16:1577. [PMID: 39771556 PMCID: PMC11678755 DOI: 10.3390/pharmaceutics16121577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND This study evaluated the long-term effectiveness and safety of a multidisciplinary early proactive therapeutic drug monitoring (TDM) program combined with Bayesian forecasting for infliximab (IFX) dose adjustment in a real-world dataset of paediatric patients with inflammatory bowel disease (IBD). METHODS A descriptive, ambispective, single-centre study of paediatric patients with IBD who underwent IFX serum concentration measurements between September 2015 and September 2023. The patients received reactive TDM before September 2019 (n = 17) and proactive TDM thereafter (n = 21). We analysed for clinical, biological, and endoscopic remission; treatment failure; hospitalisations; emergency visits; and adverse drug reactions. The IFX doses were adjusted to maintain trough concentrations ≥ 5 µg/mL, with specific targets for proactive TDM. RESULTS Of the 38 patients, 21 had Crohn's disease (CD), 16 ulcerative colitis (UC), and 1 undetermined IBD. The mean (standard deviation) IFX trough concentrations were 6.83 (5.66) µg/mL (reactive) and 12.38 (9.24) µg/mL (proactive) (p = 0.08). No statistically significant differences between groups were found in remission rates or treatment failure. The proactive group had fewer hospitalisations (14.29% vs. 23.53%; p = 0.47) and shorter median hospitalisation days (6 vs. 19; p = 0.50), although the difference was not statistically significant. The number of patients with adverse reactions (infusion related reactions and infections) was higher in the proactive group (38.10% vs. 23.53%; p = 0.34) but the difference was not significantly different. CONCLUSIONS Proactive TDM showed no significant differences in treatment outcomes compared to reactive TDM. However, the results in both the reactive and proactive TDM groups were not worse than those reported in other studies. Further studies with larger samples are needed to optimize the treatment strategies for pediatric IBD patients.
Collapse
Affiliation(s)
- Susana Clemente Bautista
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Óscar Segarra Cantón
- Paediatric Gastroenterology and Clinical Nutrition Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (Ó.S.C.); (M.Á.B.)
- Department of Paediatrics, Obstetrics and Gynaecology, Preventive Medicine and Public Health of the Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Núria Padullés-Zamora
- Pharmacy Department, Hospital Universitari de Bellvitge-IDIBELL, Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Sonia García García
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Marina Álvarez Beltrán
- Paediatric Gastroenterology and Clinical Nutrition Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (Ó.S.C.); (M.Á.B.)
| | - María Larrosa García
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Maria Josep Cabañas Poy
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Maria Teresa Sanz-Martínez
- Immunology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain;
| | - Ana Vázquez
- Department of Applied Statistics, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain;
| | - Maria Queralt Gorgas Torner
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Marta Miarons
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
- Pharmacy Department, Consorci Hospitalari de Vic, 08500 Barcelona, Spain
| |
Collapse
|
33
|
Wu D, Lin Q, Wang Z, Huang H, Song X, Gao Y, Yang X, Wen K, Sun X. Mechanism of Xue-Jie-San treating Crohn's disease complicated by atherosclerosis: Network pharmacology, molecular docking and experimental validation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156169. [PMID: 39488873 DOI: 10.1016/j.phymed.2024.156169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/29/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Crohn's disease (CD), as a chronic systemic inflammatory disease, is strongly associated with the development of premature atherosclerosis (AS). Atherosclerotic cardiovascular disease, including coronary heart disease, myocardial infarction and stroke, is a lethal complication of CD. Nowadays, there is a lack of effective monotherapy for CD complicated by AS. PURPOSE To explore the underlying effects and mechanisms of Xue-Jie-San (XJS) on treating CD complicated by AS via network pharmacology and experimental validation. METHODS The targets of XJS components were obtained from TCMSP, ETCM and PubChem databases as well as the disease genes of CD and AS from GeneCards, DisGeNET and OMIM databases. The core targets were screened out from the drug-disease common targets identified by protein-protein interaction (PPI) network analysis and then analyzed with GO and KEGG enrichment. The interaction between core target and XJS component was detected by molecular docking and molecular dynamics simulation. Subsequently, the core targets were validated via GEO datasets and their biological functions were confirmed in vitro. Nile red staining was used to evaluated lipid accumulation in human umbilical vein endothelial cells (HUVECs) challenged by lipopolysaccharide (LPS) combined with oxidized low-density lipoprotein (ox-LDL). Levels of pro-inflammatory cytokines were examined by enzyme-linked immunosorbent assay. Chemokine CCL2 and CXCL8 were detected by immunofluorescence staining. The activity of the TLR4/Myd88/NF-κB signaling pathway was assessed using Western blot. RESULTS In total, 26 common target genes of XJS, CD and AS were found. Among them, 11 core genes were identified by PPI network analysis. The effects of XJS treating CD complicated by AS were mainly mediated by the lipid and atherosclerosis pathway, inflammatory bowel disease pathway and toll-like receptor signaling pathway. Molecular docking and molecular dynamics simulation displayed strong binding affinity between XJS component and the core target. Six core genes including TLR4, IL-1β, TNF, ICAM1, CCL2 and CXCL8 were validated by GEO datasets. In vitro, the effects of XJS on reducing lipid accumulation, secretion of IL-1β, IL6, TNF-α, CCL2 and CXCL8, and the protein expressions of TLR4, Myd88, p-p65 and ICAM1 were verified. CONCLUSION XJS is a potential candidate drug for the treatment of CD complicated by AS. The underlying mechanisms involve mitigation of lipid accumulation-mediated endothelial dysfunction and blockage of immune inflammatory response by targeting TLR4.
Collapse
Affiliation(s)
- Dan Wu
- Department of Colorectal Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Qiu Lin
- Department of Colorectal Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Zhuo Wang
- Department of Clinical Laboratory, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, China
| | - Xiudao Song
- Clinical Pharmaceutical Laboratory of Traditional Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Yin Gao
- Department of Colorectal Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Xiao Yang
- Department of Colorectal Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Ke Wen
- Department of Colorectal Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China
| | - Xueliang Sun
- Department of Colorectal Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215000, China.
| |
Collapse
|
34
|
Mocci G, Tursi A, Scaldaferri F, Napolitano D, Pugliese D, Capobianco I, Bartocci B, Blasi V, Savarino EV, Maniero D, Redavid C, Lorenzon G, Cuomo A, Donnarumma L, Gravina AG, Pellegrino R, Bodini G, Pasta A, Marzo M, Serio M, Scarcelli A, Rodinò S, Sebkova L, Maconi G, Cataletti G, Luppino I, Checchin D, Ferronato A, Gaiani F, Kayali S, Felice C, Pranzo G, Catarella D, D’Agostino D, Di Bartolo E, Lombardi G, Patturelli M, Bendia E, Bolognini L, Balducci D, Quatraccioni C, Martini F, Mucherino C, D’Antonio E, Montesano L, Vespere G, Sedda S, D’Onofrio V, De Luca L, Spagnuolo R, Luzza F, Fanigliulo L, Rocco G, Sacchi C, Zampaletta C, Grossi L, Lorenzetti R, Aragona G, Perazzo P, Forti G, Allegretta L, Cazzato AI, Scorza S, Cortellini F, Capone P, Villani GD, Di Fonzo M, Iacopini F, Tonti P, Neve V, Colucci R, Elisei W, Monterubbianesi R, Faggiani R, Pica R, Pagnini C, Graziani MG, Di Paolo MC, Onidi FM, Saba F, Dore MP, Satta PU, Picchio M, Papa A. Long-Term Effectiveness and Safety of Ustekinumab in Crohn's Disease: Results from a Large Real-Life Cohort Study. J Clin Med 2024; 13:7192. [PMID: 39685651 PMCID: PMC11642252 DOI: 10.3390/jcm13237192] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/01/2024] [Accepted: 11/08/2024] [Indexed: 12/18/2024] Open
Abstract
Background: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist approved for the treatment of Crohn's disease (CD). Only limited real-life data on the long-term outcomes of CD patients treated with UST are available. This study assessed UST's long-term effectiveness and safety in a large population-based cohort of moderate to severe CD patients. Methods: This was a multicenter, retrospective, observational cohort study that included both naïve and biologic-experienced patients treated with UST who achieved clinical remission or clinical response after at least one year of treatment. Clinical activity was scored according to the Harvey-Bradshaw Index (HBI). The primary endpoints were the maintenance or achievement of clinical remission after a further 12-month period of treatment, defined as an HBI of ≤5, and safety. Other endpoints included steroid-free remission, mucosal healing (MH), steroid discontinuation, and the need for treatment optimization during the follow-up. Results: Out of 562 CD patients, after an overall 24-month follow-up, clinical remission was present in 450 (80.0%) patients, and at 12 months, clinical remission was observed in 417/437 (95.4%) patients; 33/125 (26.4%) showed clinical response at 12 months (p = 0.000). A total of 38/103 (36.9%) patients achieved MH. Only 2.1% (12/562), 3% (17/562), and 1.1% (6/562) of patients required surgery, optimization, and re-induction, respectively. Adverse events occurred in eight patients (1.42%). According to a multivariate analysis, the only predictor of long-term remission was the presence of remission at the 12-month follow-up (p = 0.000). Conclusions: Long-term treatment with UST presents good efficacy and safety profiles in CD patients, especially for patients who achieve remission after one year.
Collapse
Affiliation(s)
- Giammarco Mocci
- Division of Gastroenterology, AORN “Brotzu” Hospital, 09124 Cagliari, Italy; (G.M.); (F.M.O.); (F.S.); (P.U.S.)
| | - Antonio Tursi
- Territorial Gastroenterology Service, ASL BAT, 76123 Andria, Italy
- Department of Medical and Surgical Sciences, Catholic University, School of Medicine, 00168 Rome, Italy
| | - Franco Scaldaferri
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
- School of Medicine, Catholic University, 00168 Rome, Italy
| | - Daniele Napolitano
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
| | - Daniela Pugliese
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
- School of Medicine, Catholic University, 00168 Rome, Italy
| | - Ivan Capobianco
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
| | - Bianca Bartocci
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
| | - Valentina Blasi
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
| | - Edoardo V. Savarino
- Gastroenterology Unit, Azienda Ospedale-Università di Padova (AOUP), 35100 Padua, Italy; (E.V.S.); (D.M.); (C.R.); (G.L.)
| | - Daria Maniero
- Gastroenterology Unit, Azienda Ospedale-Università di Padova (AOUP), 35100 Padua, Italy; (E.V.S.); (D.M.); (C.R.); (G.L.)
| | - Carlo Redavid
- Gastroenterology Unit, Azienda Ospedale-Università di Padova (AOUP), 35100 Padua, Italy; (E.V.S.); (D.M.); (C.R.); (G.L.)
| | - Greta Lorenzon
- Gastroenterology Unit, Azienda Ospedale-Università di Padova (AOUP), 35100 Padua, Italy; (E.V.S.); (D.M.); (C.R.); (G.L.)
| | - Antonio Cuomo
- Division of Gastroenterology, “Umberto I” Hospital, 84014 Nocera Inferiore, Italy; (A.C.); (L.D.)
| | - Laura Donnarumma
- Division of Gastroenterology, “Umberto I” Hospital, 84014 Nocera Inferiore, Italy; (A.C.); (L.D.)
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine, Hepatogastroenterology and Digestive Endoscopy Unit, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.G.); (R.P.)
| | - Raffaele Pellegrino
- Department of Precision Medicine, Hepatogastroenterology and Digestive Endoscopy Unit, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.G.G.); (R.P.)
| | - Giorgia Bodini
- Department of Internal Medicine and Medical Specialties, Division of Gastroenterology, IRCCS “San Martino” Hospital, University of Genoa, 86100 Genoa, Italy; (G.B.); (A.P.)
| | - Andrea Pasta
- Department of Internal Medicine and Medical Specialties, Division of Gastroenterology, IRCCS “San Martino” Hospital, University of Genoa, 86100 Genoa, Italy; (G.B.); (A.P.)
| | - Manuela Marzo
- Division of Gastroenterology, “Veris-Delli Ponti” Hospital, 73020 Scorrano, Italy;
| | - Mariaelena Serio
- Division of Gastroenterology, “San Salvatore” Hospital, 61121 Pesaro, Italy; (M.S.); (A.S.)
| | - Antonella Scarcelli
- Division of Gastroenterology, “San Salvatore” Hospital, 61121 Pesaro, Italy; (M.S.); (A.S.)
| | - Stefano Rodinò
- Division of Gastroenterology, “Ciaccio-Pugliese” Hospital, 88100 Catanzaro, Italy; (S.R.); (L.S.)
| | - Ladislava Sebkova
- Division of Gastroenterology, “Ciaccio-Pugliese” Hospital, 88100 Catanzaro, Italy; (S.R.); (L.S.)
| | - Giovanni Maconi
- Gastroenterology Unit, Department Biomedical and Clinical Sciences, “L. Sacco” University Hospital, 20100 Milan, Italy; (G.M.); (G.C.)
| | - Giovanni Cataletti
- Gastroenterology Unit, Department Biomedical and Clinical Sciences, “L. Sacco” University Hospital, 20100 Milan, Italy; (G.M.); (G.C.)
| | - Ileana Luppino
- Division of Gastroenterology, “Annunziata” Hospital, 87100 Cosenza, Italy;
| | - Davide Checchin
- Division of Gastroenterology, “S Giovanni e Paolo” Hospital, 30100 Mestre−Venezia, Italy;
| | | | - Federica Gaiani
- Gastroenterology and Endoscopy Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.)
| | - Stefano Kayali
- Gastroenterology and Endoscopy Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.)
| | - Carla Felice
- Division of Internal Medicine, “Ca’ Foncello” University Hospital, 31100 Treviso, Italy;
| | - Giuseppe Pranzo
- Ambulatory for IBD Treatment, “Valle D’Itria” Hospital, 74015 Martina Franca, Italy;
| | - Domenico Catarella
- Division of Gastroenterology, ARNAS “Garibaldi”, 95100 Catania, Italy; (D.C.); (D.D.); (E.D.B.)
| | - Dario D’Agostino
- Division of Gastroenterology, ARNAS “Garibaldi”, 95100 Catania, Italy; (D.C.); (D.D.); (E.D.B.)
| | - Elisabetta Di Bartolo
- Division of Gastroenterology, ARNAS “Garibaldi”, 95100 Catania, Italy; (D.C.); (D.D.); (E.D.B.)
| | - Giovanni Lombardi
- Division of Gastroenterology, AORN “Cardarelli”, 80131 Naples, Italy; (G.L.); (M.P.)
| | - Marta Patturelli
- Division of Gastroenterology, AORN “Cardarelli”, 80131 Naples, Italy; (G.L.); (M.P.)
| | - Emanuele Bendia
- Division of Digestive Diseases, Digestive Endoscopy and Inflammatory Bowel Diseases, A.O. “Ospedali Riuniti”, 60121 Ancona, Italy; (E.B.); (L.B.); (C.Q.); (F.M.)
| | - Laura Bolognini
- Division of Digestive Diseases, Digestive Endoscopy and Inflammatory Bowel Diseases, A.O. “Ospedali Riuniti”, 60121 Ancona, Italy; (E.B.); (L.B.); (C.Q.); (F.M.)
| | - Daniele Balducci
- Division of Digestive Diseases, Digestive Endoscopy and Inflammatory Bowel Diseases, A.O. “Ospedali Riuniti”, 60121 Ancona, Italy; (E.B.); (L.B.); (C.Q.); (F.M.)
| | - Claudia Quatraccioni
- Division of Digestive Diseases, Digestive Endoscopy and Inflammatory Bowel Diseases, A.O. “Ospedali Riuniti”, 60121 Ancona, Italy; (E.B.); (L.B.); (C.Q.); (F.M.)
| | - Francesco Martini
- Division of Digestive Diseases, Digestive Endoscopy and Inflammatory Bowel Diseases, A.O. “Ospedali Riuniti”, 60121 Ancona, Italy; (E.B.); (L.B.); (C.Q.); (F.M.)
| | - Caterina Mucherino
- Division of Gastroenterology, Azienda Ospedaliera “S. Anna e S. Sebastiano”, 81100 Caserta, Italy; (C.M.); (E.D.); (L.M.)
| | - Elvira D’Antonio
- Division of Gastroenterology, Azienda Ospedaliera “S. Anna e S. Sebastiano”, 81100 Caserta, Italy; (C.M.); (E.D.); (L.M.)
| | - Laura Montesano
- Division of Gastroenterology, Azienda Ospedaliera “S. Anna e S. Sebastiano”, 81100 Caserta, Italy; (C.M.); (E.D.); (L.M.)
| | - Giuliana Vespere
- Division of Gastroenterology, “Ospedale del Mare”, 80147 Naples, Italy; (G.V.); (S.S.); (V.D.); (L.D.L.)
| | - Silvia Sedda
- Division of Gastroenterology, “Ospedale del Mare”, 80147 Naples, Italy; (G.V.); (S.S.); (V.D.); (L.D.L.)
| | - Vittorio D’Onofrio
- Division of Gastroenterology, “Ospedale del Mare”, 80147 Naples, Italy; (G.V.); (S.S.); (V.D.); (L.D.L.)
| | - Leonardo De Luca
- Division of Gastroenterology, “Ospedale del Mare”, 80147 Naples, Italy; (G.V.); (S.S.); (V.D.); (L.D.L.)
| | - Rocco Spagnuolo
- Department of Health Science, University of Catanzaro, 88100 Catanzaro, Italy; (R.S.); (F.L.)
| | - Francesco Luzza
- Department of Health Science, University of Catanzaro, 88100 Catanzaro, Italy; (R.S.); (F.L.)
| | - Libera Fanigliulo
- Division of Gastroenterology, “S.S. Annunziata” Hospital, 74121 Taranto, Italy;
| | - Giulia Rocco
- Division of Gastroenterology, “Belcolle” Hospital, 01100 Viterbo, Italy; (G.R.); (C.S.); (C.Z.)
| | - Carlotta Sacchi
- Division of Gastroenterology, “Belcolle” Hospital, 01100 Viterbo, Italy; (G.R.); (C.S.); (C.Z.)
| | - Costantino Zampaletta
- Division of Gastroenterology, “Belcolle” Hospital, 01100 Viterbo, Italy; (G.R.); (C.S.); (C.Z.)
| | - Laurino Grossi
- Gastroenterology Unit, “Spirito Santo” Hospital, “G d’Annunzio” University, 65121 Pescara, Italy;
| | - Roberto Lorenzetti
- Division of Gastroenterology, “Nuovo Regina Margherita” Territorial Hospital, 00153 Rome, Italy;
| | - Giovanni Aragona
- Division of Gastroenterology, “Guglielmo da Saliceto” Hospital, 29121 Piacenza, Italy; (G.A.); (P.P.)
| | - Patrizia Perazzo
- Division of Gastroenterology, “Guglielmo da Saliceto” Hospital, 29121 Piacenza, Italy; (G.A.); (P.P.)
| | - Giacomo Forti
- Division of Digestive Endoscopy, “S. Maria Goretti” Hospital, 04100 Latina, Italy;
| | - Leonardo Allegretta
- Division of Gastroenterology, “Santa Caterina Novella” Hospital, 73013 Galatina, Italy; (L.A.); (A.I.C.); (S.S.)
| | - Alessia Immacolata Cazzato
- Division of Gastroenterology, “Santa Caterina Novella” Hospital, 73013 Galatina, Italy; (L.A.); (A.I.C.); (S.S.)
| | - Stefano Scorza
- Division of Gastroenterology, “Santa Caterina Novella” Hospital, 73013 Galatina, Italy; (L.A.); (A.I.C.); (S.S.)
| | - Fabio Cortellini
- Division of Gastroenterology, “Infermi” Hospital, 47921 Rimini, Italy;
| | - Pietro Capone
- Division of Gastroenterology, “T. Maresca” Hospital, 80059 Torre del Greco, Italy; (P.C.); (G.D.V.)
| | - Guido Daniele Villani
- Division of Gastroenterology, “T. Maresca” Hospital, 80059 Torre del Greco, Italy; (P.C.); (G.D.V.)
| | - Michela Di Fonzo
- Division of Gastroenterology, “Ospedale dei Castelli”, 00040 Ariccia, Italy; (M.D.F.); (F.I.)
| | - Federico Iacopini
- Division of Gastroenterology, “Ospedale dei Castelli”, 00040 Ariccia, Italy; (M.D.F.); (F.I.)
| | - Paolo Tonti
- Division of Gastroenterology, “A. Perrino” Hospital, 72100 Brindisi, Italy; (P.T.); (V.N.)
| | - Viviana Neve
- Division of Gastroenterology, “A. Perrino” Hospital, 72100 Brindisi, Italy; (P.T.); (V.N.)
| | - Raffaele Colucci
- Digestive Endoscopy Unit, “San Matteo degli Infermi” Hospital, 06049 Spoleto, Italy;
| | - Walter Elisei
- Division of Gastroenterology, A.O. “S. Camillo-Folanini”, 00152 Rome, Italy; (W.E.); (R.M.); (R.F.)
| | - Rita Monterubbianesi
- Division of Gastroenterology, A.O. “S. Camillo-Folanini”, 00152 Rome, Italy; (W.E.); (R.M.); (R.F.)
| | - Roberto Faggiani
- Division of Gastroenterology, A.O. “S. Camillo-Folanini”, 00152 Rome, Italy; (W.E.); (R.M.); (R.F.)
| | - Roberta Pica
- Division of Gastroenterology, IBD Unit, “S. Pertini” Hospital, 00157 Rome, Italy;
| | - Cristiano Pagnini
- Division of Gastroenterology, “S. Giovanni-Addolorata” Hospital, 00184 Rome, Italy; (C.P.); (M.G.G.); (M.C.D.P.)
| | - Maria Giovanna Graziani
- Division of Gastroenterology, “S. Giovanni-Addolorata” Hospital, 00184 Rome, Italy; (C.P.); (M.G.G.); (M.C.D.P.)
| | - Maria Carla Di Paolo
- Division of Gastroenterology, “S. Giovanni-Addolorata” Hospital, 00184 Rome, Italy; (C.P.); (M.G.G.); (M.C.D.P.)
| | - Francesca Maria Onidi
- Division of Gastroenterology, AORN “Brotzu” Hospital, 09124 Cagliari, Italy; (G.M.); (F.M.O.); (F.S.); (P.U.S.)
| | - Francesco Saba
- Division of Gastroenterology, AORN “Brotzu” Hospital, 09124 Cagliari, Italy; (G.M.); (F.M.O.); (F.S.); (P.U.S.)
| | - Maria Pina Dore
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy;
| | - Paolo Usai Satta
- Division of Gastroenterology, AORN “Brotzu” Hospital, 09124 Cagliari, Italy; (G.M.); (F.M.O.); (F.S.); (P.U.S.)
| | - Marcello Picchio
- Division of General Surgery, “P. Colombo” Hospital, ASL Roma 6, 00049 Velletri, Italy;
| | - Alfredo Papa
- Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (F.S.); (D.N.); (D.P.); (I.C.); (B.B.); (V.B.); (A.P.)
- School of Medicine, Catholic University, 00168 Rome, Italy
| |
Collapse
|
35
|
Kemp K, Samaan MA, Verma AM, Lobo AJ. Crohn's disease management: translating STRIDE-II for UK clinical practice. Therap Adv Gastroenterol 2024; 17:17562848241280885. [PMID: 39526077 PMCID: PMC11544685 DOI: 10.1177/17562848241280885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/19/2024] [Indexed: 11/16/2024] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) characterised by endoscopic inflammation, progressive bowel damage and gastrointestinal lesions. Although treatment strategies for CD have traditionally focused on a stepwise pharmacological approach to achieve clinical remission or symptom resolution, these treatment goals correlate poorly with disease activity. Thus, achieving full clinical remission and full endoscopic healing alone may be insufficient, as patients may remain at risk of inflammatory complications. Individualised 'treat-to-target' (T2T) pharmacological and treatment approaches represent a promising strategy for improving endoscopic remission and symptom resolution among patients with CD. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) and STRIDE-II guidelines, launched in 2013 and later renewed, identified individualised targets for a T2T therapeutic approach for patients with IBD. These guidelines facilitate the individualisation of target treatment goals through evidence-based, long-term (health-related quality of life, absence of disability, endoscopic healing) and intermediate/short-term (abdominal pain, stool frequency, normalisation of biomarker levels) treatment targets, allowing patients and clinicians to consider the risk-to-benefit balance of goals and selected therapeutic strategies. This article aims to summarise the STRIDE-II guidelines and provide intellectual guidance for healthcare professionals to apply the STRIDE-II principles to current clinical practice in the United Kingdom (UK). Management recommendations for primary and secondary first-line non-responders are provided, along with suggestions for utilising the endoscopic outcomes scoring system in UK clinical practice.
Collapse
Affiliation(s)
- Karen Kemp
- Department of Gastroenterology, Manchester Clinical Academic Centre, Manchester Royal Infirmary, University of Manchester, Oxford Road, Manchester M13 9WL, UK
| | - Mark A. Samaan
- Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK
| | - Ajay M. Verma
- Kettering General Hospital NHS Foundation Trust, Kettering, UK
| | - Alan J. Lobo
- Inflammatory Bowel Disease Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Broomhill, Sheffield, UK
| |
Collapse
|
36
|
Fernandes SR, Bernardo S, Saraiva S, Rita Gonçalves A, Moura Santos P, Valente A, Araújo Correia L, Cortez-Pinto H, Magro F. Proactive Infliximab Monitoring Improves the Rates of Transmural Remission in Crohn's Disease: A Propensity Score-Matched Analysis. Inflamm Bowel Dis 2024; 30:1974-1982. [PMID: 37982426 DOI: 10.1093/ibd/izad272] [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: 08/03/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Few patients can reach transmural remission in Crohn's disease (CD) with currently available therapies. Proactive optimization of infliximab (IFX) based on trough levels may potentially improve these results. METHODS Retrospective cohort study including consecutive CD patients starting treatment with IFX. Rates of transmural remission were compared between patients with and without therapeutic drug monitoring (target level: 5-7 µg/mL). A propensity score-matched analysis was performed to adjust for potential confounders. RESULTS A total of 195 CD patients were included, 57.9% receiving proactive therapeutic drug monitoring. The rates of transmural remission were higher in patients under proactive therapeutic drug monitoring (37.2% vs 18.3%; P = .004) with similar results in the propensity score-matched analysis (34.2% vs 17.1%; P = .025). In multivariate analysis, proactive therapeutic drug monitoring was independently associated with transmural remission (odds ratio, 2.95; 95% confidence interval, 1.44-6.06; P = .003). CONCLUSIONS Proactive optimization of IFX based on trough levels increases the rates of transmural remission in CD.
Collapse
Affiliation(s)
- Samuel Raimundo Fernandes
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Sónia Bernardo
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Sofia Saraiva
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Ana Rita Gonçalves
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Paula Moura Santos
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Ana Valente
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
| | - Luís Araújo Correia
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia da Faculdade de Medicina de Lisboa, Lisbon, Portugal
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
- Portuguese Group of Studies in Inflammatory Bowel Disease, Gedii, Porto, Portugal
| |
Collapse
|
37
|
Atia O, Friss C, Focht G, Magen Rimon R, Ledderman N, Ben-Tov A, Loewenberg Weisband Y, Matz E, Gorelik Y, Chowers Y, Dotan I, Turner D. Durability of Adalimumab and Infliximab in Children With Crohn's Disease: A Nationwide Comparison From the epi-IIRN Cohort. Inflamm Bowel Dis 2024; 30:2097-2104. [PMID: 38190498 DOI: 10.1093/ibd/izad301] [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: 03/03/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND In a nationwide cohort, we aimed to compare the durability of infliximab and adalimumab as first biologic treatment in children with Crohn's disease (CD), stratified as combotherapy or monotherapy. METHODS We used data from the epi-IIRN cohort that includes all patients with inflammatory bowel diseases in Israel. Durability was defined as consistent treatment without surgery or treatment escalation. All comparisons followed stringent propensity-score matching in Cox proportional hazard models. RESULTS Of the 3487 children diagnosed with CD since 2005, 2157 (62%) received biologics (1127 [52%] infliximab, 964 [45%] adalimumab and 52 [2%] vedolizumab as first biologic), representing a higher proportion than that among adults diagnosed during the same time period (5295 of 15 776 [34%]; P < .001). Time from diagnosis to initiation of biologic was shorter in pediatric-onset compared with adult-onset disease (median time during the last 3 years was 2.7 months [interquartile range 1.2-5.4] vs 5.2 months [2.6-8.9]; P < .001). The durability of adalimumab monotherapy after 1 and 5 years from initiation of treatment was better than infliximab monotherapy (79%/54% vs 67%/37%, respectively; n = 452 matched children; hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.3-2.3; P < .001), while in those treated with combotherapy, durability was similar (94%/66% with infliximab vs 90%/54% with adalimumab; n = 100; HR, 1.7; 95% CI, 0.9-3.3; P = .1). Durability was higher in children treated with infliximab combotherapy vs infliximab monotherapy (87%/45% vs 75%/39%; n = 440; HR, 1.4; 95% CI, 1.1-1.8; P = .01). The durability of adalimumab monotherapy was similar to infliximab combotherapy (83%/53% vs 89%/56%, respectively; n = 238; HR, 0.9; 95% CI, 0.7-1.2; P = .4). CONCLUSION Our results support using adalimumab monotherapy as a first-line biologic in children with CD. When infliximab is used, combotherapy may be advantageous over monotherapy.
Collapse
Affiliation(s)
- Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
| | - Chagit Friss
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
| | - Gili Focht
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
| | - Ramit Magen Rimon
- Pediatric Gastroenterology & Nutrition institute, Ruth Rappaport Children's Hospital, Rambam Medical Center, Faculty of Medicine, Technion, Haifa, Israel
| | | | - Amir Ben-Tov
- Kahn Sagol Maccabi Research and Innovation Center, Maccabi Healthcare Services, Tel-Aviv, Israel
- The Faculty of Medicine, Tel Aviv University, Israel
| | | | - Eran Matz
- Leumit Health Services, Tel-Aviv, Israel
| | - Yuri Gorelik
- Technion Israel Institute of Technology, Department of Gastroenterology, Rambam Healthcare Campus, Bruce Rappaport School of Medicine, Haifa, Israel
| | - Yehuda Chowers
- Technion Israel Institute of Technology, Department of Gastroenterology, Rambam Healthcare Campus, Bruce Rappaport School of Medicine, Haifa, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
- The Faculty of Medicine, Tel Aviv University, Israel
| | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
| |
Collapse
|
38
|
Hoelz H, Bragagna L, Litwin A, Koletzko S, Le Thi TG, Schwerd T. Pediatric IBD Patients Treated With Infliximab and Proactive Drug Monitoring Benefit From Early Concomitant Immunomodulatory Therapy: A Retrospective Analysis of a 10-Year Real-Life Cohort. Inflamm Bowel Dis 2024; 30:2004-2018. [PMID: 38011813 DOI: 10.1093/ibd/izad277] [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: 07/27/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Limited approval of second-line treatments in pediatric inflammatory bowel disease (pIBD) necessitates optimized use of infliximab (IFX) with proactive therapeutic drug monitoring (TDM). We investigated whether early combo-therapy with an immunomodulator (IMM) provides additional benefit. METHODS In the retrospectively reviewed medical records of all children treated with IFX and proactive TDM between 2013 and 2022, IMMearly (IMM ≤3 months since IFX start) was evaluated against IMMother/no (late/short or no IMM) over follow-up of 3 to 60 months. Kaplan-Meier analysis was used to analyze time to loss of response (LOR) with IFX discontinuation or time to antibodies-to-IFX (ATI) development. RESULTS Three hundred fifteen patients with pIBD were reviewed; of those, 127 with 2855 visits were included (77 CD, 50 UC/IBD-unclassified). Sixty patients received IMMearly, 20 patients IMMother, and 47 had IFX monotherapy. Median follow-up time was 30 and 26 months for IMMearly and IMMother/no, respectively, with comparable proactive TDM. Infliximab treatment persistence was 68% after 60 months. Loss of response was observed in 7 IMMearly and 15 IMMother/no patients (P = .16). Early combo-therapy significantly delayed LOR with IFX discontinuation (median LOR free interval IMMearly 30 months vs IMMother/no 9 months, P = .01). Patients with IMMother/no were 10-, 3- and 2-times more likely to experience LOR with IFX discontinuation after 1, 3, and 5 years, respectively. There were no significant group differences regarding the presence of any positive (>10 arbitrary units per milliliter [AU/mL]) or high (>100 AU/mL) ATI, median ATI concentrations, and ATI-free interval. CONCLUSIONS Early IMM combo-therapy in proactively monitored patients with pIBD significantly prolonged the median LOR free interval compared with late/short or no IMM treatment.
Collapse
Affiliation(s)
- Hannes Hoelz
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
| | - Lena Bragagna
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
| | - Anna Litwin
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
| | - Sibylle Koletzko
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Thu Giang Le Thi
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
| | - Tobias Schwerd
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany
| |
Collapse
|
39
|
Gros B, Blackwell J, Segal J, Black CJ, Ford AC, Din S. Harms with placebo in trials of biological therapies and small molecules as maintenance therapy in inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2024; 9:1030-1040. [PMID: 39307146 DOI: 10.1016/s2468-1253(24)00233-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Randomised placebo-controlled trials for the induction of inflammatory bowel disease (IBD) remission involve potential harms to those receiving placebo. Whether these harms are also apparent with placebo during maintenance of remission trials in IBD is unclear. We aimed to examine the potential harms associated with receiving placebo in trials of licensed biologics and small molecules for maintenance of remission of ulcerative colitis and luminal Crohn's disease in a meta-analysis. METHODS We performed a systematic review and meta-analysis. We searched several medical literature databases including MEDLINE (from Jan 1, 1946, to May 31, 2024), Embase and Embase Classic (Jan 1, 1947, to May 31, 2024), and the Cochrane Central Register of Controlled Trials from database inception to May 31, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for maintenance of remission in adults with IBD reporting data on adverse events over a period of 20 weeks or more. There were no language restrictions or prespecified exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, drug-related adverse event, infection, worsening of IBD activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events, reporting relative risks (RRs) for placebo versus active drug with 95% CIs for each outcomes. The protocol for this meta-analysis was registered with PROSPERO (CRD42024542624). FINDINGS Our search identified 10 826 citations, of which 45 trials including 16 562 patients (10 319 [62·3%] receiving active drug and 6243 [37·7%] placebo) were eligible. The risks of any treatment-emergent adverse event (7297/9546 [76·4%] patients on active drug vs 4415/5850 [75·5%] on placebo; RR 1·01, 95% CI 0·99-1·04; I2 =47%), serious infection (260/10 242 [2·5%] vs 155/6149 [2·5%]; 0·97, 0·79-1·19; I2 =0%), or venous thromboembolic event (12/4729 [0·3%] vs 9/2691 [0·3%]; 0·72, 0·31-1·66; I2 =0%) were not significantly lower with active drug than placebo. The risks of any infection (3208/8038 [39·9%] vs 1713/4809 [35·6%]; 1·14, 1·05-1·23; I2 =60%) or any drug-related adverse event (1094/2997 [36·5%] vs 609/1950 [31·2%]; 1·24, 1·02-1·50; I2 =75%) were higher with active drug than placebo. However, the risks of any worsening of IBD activity (1038/8090 [12·8%] vs 1181/5191 [22·8%]; 0·58, 0·52-0·64; I2 =40%), any withdrawal due to adverse events (610/10 282 [5·9%] vs 561/6207 [9·0%]; 0·71, 0·60-0·84; I2 =43%), any serious adverse events (1066/10 292 [10·4%] vs 742/6198 [12·0%]; 0·85, 0·77-0·94; I2 =17%), or any serious worsening of IBD activity (101/5707 [1·8%] vs 143/3640 [3·9%]; 0·55, 0·42-0·71; I2 =0%) were lower with active drug than placebo. 21 randomised controlled trials were judged as low risk of bias across all domains. INTERPRETATION In maintenance of remission trials in IBD, placebo was associated with some clinically significant potential harms. Patients should be counselled about these before participating in clinical trials and consideration given to alternative designs to test novel drugs in IBD. FUNDING None.
Collapse
Affiliation(s)
- Beatriz Gros
- Department of Gastroenterology, Reina Sofía University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Cordoba, University of Cordoba, Cordoba, Spain; Biomedical Research Center in Hepatic and Digestive Disease, CIBEREHD, Madrid, Spain
| | - Jonathan Blackwell
- Edinburgh Inflammatory Bowel Diseases Unit, Western General Hospital, Edinburgh, UK
| | - Jonathan Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Christopher J Black
- Leeds Gastroenterology Institute, St James's University Hospital, University of Leeds, Leeds, UK; Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, University of Leeds, Leeds, UK; Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Shahida Din
- Edinburgh Inflammatory Bowel Diseases Unit, Western General Hospital, Edinburgh, UK; Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK.
| |
Collapse
|
40
|
Yu N, Lee T, Tassone D, Vogrin S, Phan S, Wu DM, Zhang J, Wang L, Tjahyadi J, Dutt K, Liou H, Basnayake C, Wright E, Niewiadomski O, Lust M, Schulberg J, Kamm MA, Connell W, Thompson AJ, Hilmi I, Raja Ali RA, Wei SC, De Cruz P, Friedman AB, Moore GT, Van Langenberg D, Ding NS. 6-Thioguanine nucleotide levels are associated with infliximab but not adalimumab levels in inflammatory bowel disease patients on combination therapy. Intern Med J 2024; 54:1856-1866. [PMID: 39234975 DOI: 10.1111/imj.16504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/31/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION 6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.
Collapse
Affiliation(s)
- Natalie Yu
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Tanya Lee
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Daniel Tassone
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Sara Vogrin
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Steven Phan
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
| | - Damien M Wu
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
| | - Jason Zhang
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - Luke Wang
- Department of Gastroenterology, Monash Health, Melbourne, Victoria, Australia
| | - Jason Tjahyadi
- Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
| | - Krishneel Dutt
- Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
| | - Hana Liou
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chamara Basnayake
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Emily Wright
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Ola Niewiadomski
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Mark Lust
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Julien Schulberg
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Michael A Kamm
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - William Connell
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Alexander J Thompson
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Ida Hilmi
- Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Raja A Raja Ali
- Department of Medicine, Hospital Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Shu C Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Peter De Cruz
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
| | - Antony B Friedman
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - Gregory T Moore
- Department of Gastroenterology, Monash Health, Melbourne, Victoria, Australia
- Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Daniel Van Langenberg
- Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
- Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Nik S Ding
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| |
Collapse
|
41
|
Moses J, Adler J, Saeed SA, Firestine AM, Galanko JA, Ammoury RF, Bass DM, Bass JA, Bastidas M, Benkov KJ, Bousvaros A, Cabrera JM, Chun KY, Dorsey JM, Ebach DR, Gulati AS, Herfarth HH, Ivanova A, Jester TW, Kaplan JL, Kusek ME, Leibowitz IH, Linville TM, Margolis PA, Minar P, Molle-Rios Z, Niklinska-Schirtz BJ, Olano KK, Osaba L, Palomo PJ, Pashankar DS, Pitch L, Samson CM, Sandberg KC, Steiner SJ, Strople JA, Sullivan JS, Tung J, Wali P, Wohl DA, Zikry M, Boyle BM, Kappelman MD. Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease. Inflamm Bowel Dis 2024:izae239. [PMID: 39418336 DOI: 10.1093/ibd/izae239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). METHODS We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. RESULTS Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). CONCLUSIONS LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.
Collapse
Affiliation(s)
- Jonathan Moses
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA
| | - Jeremy Adler
- Division of Gastroenterology, Hepatology, and Nutrition, C.S. Mott's Children's Hospital, Ann Arbor, MI, USA
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, MI, USA
| | - Shehzad A Saeed
- Department of Medical Affairs, Dayton Children's Hospital and Wright State University, Dayton, OH, USA
| | - Ann M Firestine
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Joseph A Galanko
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rana F Ammoury
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, VA, USA
| | - Dorsey M Bass
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA
| | - Julie A Bass
- Department of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, USA
| | | | - Keith J Benkov
- Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, NY, USA
| | - Athos Bousvaros
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - José M Cabrera
- Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Kelly Y Chun
- Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA
| | - Jill M Dorsey
- Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Specialty Care, Jacksonville, FL, USA
| | - Dawn R Ebach
- Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Ajay S Gulati
- Department of Pediatrics and Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hans H Herfarth
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anastasia Ivanova
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Traci W Jester
- Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jess L Kaplan
- Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, MA, USA
| | - Mark E Kusek
- Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ian H Leibowitz
- Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, D.C., USA
| | - Tiffany M Linville
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, NC, USA
| | - Peter A Margolis
- Cincinnati Children's Research Foundation Chair in Improvement Science, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Phillip Minar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Zarela Molle-Rios
- Division of Pediatric Gastroenterology, Nemours Children's Hospital, Wilmington, DE, USA
| | - Barbara Joanna Niklinska-Schirtz
- Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Kelly K Olano
- Division of Biostatistics and Epidemiology, Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Lourdes Osaba
- Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain
| | - Pablo J Palomo
- Division of Pediatric Gastroenterology, Nemours Children's Hospital, Orlando, FL, USA
| | - Dinesh S Pashankar
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Lisa Pitch
- ImproveCareNow Inc., Essex Junction, VT, USA
| | - Charles M Samson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
| | - Kelly C Sandberg
- Division of Gastroenterology, Hepatology, and Nutrition, Dayton Children's Hospital, Dayton, OH, USA
| | - Steven J Steiner
- Division of Pediatric Gastroenterology, Hepatology & Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jennifer A Strople
- Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Jillian S Sullivan
- The University of Vermont Children's Hospital and Department of Pediatrics, Larner College of Medicine, The University of Vermont, Burlington, VT, USA
| | - Jeanne Tung
- University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, OK, USA
| | - Prateek Wali
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, NY, USA
| | - David A Wohl
- Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mike Zikry
- Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA
| | - Brendan M Boyle
- Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - Michael D Kappelman
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| |
Collapse
|
42
|
Navajas Hernández P, Mouhtar el Halabi S, González Parra AC, Valdés Delgado T, Maldonado Pérez B, Castro Laria L, Charpentier C, Argüelles-Arias F. Carriage of the HLA-DQA1⋆05 haplotype is associated with a higher risk of infratherapeutic drug concentration and higher immunogenicity in patients undergoing treatment with anti-TNF for inflammatory bowel disease. Therap Adv Gastroenterol 2024; 17:17562848241278145. [PMID: 39421002 PMCID: PMC11483697 DOI: 10.1177/17562848241278145] [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: 03/14/2024] [Accepted: 08/11/2024] [Indexed: 10/19/2024] Open
Abstract
Background The success of anti-tumor necrosis factor (TNF) drug strategies in the treatment of inflammatory bowel disease (IBD) is altered by the development of anti-drug antibodies that reduce their efficacy. Studies have shown that the HLA-DQA1⋆05 allele increases the risk of immunogenicity to anti-TNF drugs approximately twofold. Objective Analyze whether the presence of the HLA-DQA1⋆05 allele is associated with the development of immunogenicity and to evaluate the disease response to anti-TNF drugs (infliximab (IFX) and adalimumab (ADA)), according to the presence of this allele. Design This is an observational retrospective cohort study, single center, to determine the impact of HLA-DQA1⋆05 on disease activity in patients with IBD at the Hospital Universitario Virgen Macarena. Methods In total, 200 IBD patients were included: 109 treated with IFX and 91 with ADA. Data were collected using the computerized medical records from the DIRAYA program of the Servicio Andaluz de Salud. Response-defined as improvement-and remission-defined as the disappearance of symptoms and analytical/endoscopic signs-were assessed using activity indices (partial Mayo, Harvey-Bradshaw) in all patients. Anti-TNF drug levels were also determined, as well as the presence or absence of anti-IFX and anti-ADA antibodies. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement. Results The HLA-DQA1⋆05 haplotype was present in 70 (35%) patients, including 39 (36%) treated with IFX and 31 (34%) with ADA. The risk of withdrawal, intensification, as well as antibody development, was higher in patients carrying the allele and on treatment with IFX or ADA. Conclusion In our study, we demonstrated that there is an increased risk of immunogenicity in patients carrying the HLA-DQA1⋆05 genotype, which would support the idea of screening for this genetic variant before starting anti-TNF therapy, as its prevalence is high in the general population and increases the risk of treatment discontinuation due to loss of response.
Collapse
Affiliation(s)
- Pilar Navajas Hernández
- Department of Gastroenterology, Hospital Universitario Virgen Macarena, Av. Dr. Fedriani, 3, Seville 41009, Spain
| | | | | | | | | | | | - Cloé Charpentier
- University Hospital of Rouen Hepato-Gastroenterology Department, Rouen, Normandy, France
| | - Federico Argüelles-Arias
- Virgen Macarena University Hospital, Sevilla, Spain
- Federico Argüelles-Arias is also affiliated to Universidad de Sevilla
| |
Collapse
|
43
|
Gordon H, Minozzi S, Kopylov U, Verstockt B, Chaparro M, Buskens C, Warusavitarne J, Agrawal M, Allocca M, Atreya R, Battat R, Bettenworth D, Bislenghi G, Brown SR, Burisch J, Casanova MJ, Czuber-Dochan W, de Groof J, El-Hussuna A, Ellul P, Fidalgo C, Fiorino G, Gisbert JP, Sabino JG, Hanzel J, Holubar S, Iacucci M, Iqbal N, Kapizioni C, Karmiris K, Kobayashi T, Kotze PG, Luglio G, Maaser C, Moran G, Noor N, Papamichael K, Peros G, Reenaers C, Sica G, Sigall-Boneh R, Vavricka SR, Yanai H, Myrelid P, Adamina M, Raine T. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis 2024; 18:1531-1555. [PMID: 38877997 DOI: 10.1093/ecco-jcc/jjae091] [Citation(s) in RCA: 62] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Indexed: 07/28/2024]
Affiliation(s)
- Hannah Gordon
- Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, UK
| | - Silvia Minozzi
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
| | - Bram Verstockt
- Department Gastroenterology & Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - María Chaparro
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Christianne Buskens
- Department of Surgery, Amsterdam UMC, Location VUMC, Amsterdam, The Netherlands
| | | | - Manasi Agrawal
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Mariangela Allocca
- IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Gastroenterology and Endoscopy, Milan, Italy
| | - Raja Atreya
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Robert Battat
- Division of Gastroenterology, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | - Dominik Bettenworth
- CED Schwerpunktpraxis, Münster and Medical Faculty of the University of Münster, Münster, Germany
| | - Gabriele Bislenghi
- Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
| | | | - Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults; Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - María José Casanova
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Wladyslawa Czuber-Dochan
- Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK
| | - Joline de Groof
- Colorectal Surgery, Royal Surrey NHS Foundation Trust, Guildford, UK
| | - Alaa El-Hussuna
- Department of Surgery, OpenSourceResearch Organization [OSRC.Network], Aalborg, Denmark
| | - Pierre Ellul
- Division of Gastroenterology, Mater Dei Hospital, L-Imsida, Malta
| | - Catarina Fidalgo
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
- Division of Gastroenterology, Hospital da Luz, Lisboa, Portugal
| | | | - Javier P Gisbert
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - João Guedelha Sabino
- Department Gastroenterology & Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Jurij Hanzel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Stefan Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Nusrat Iqbal
- Department of Surgery, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | | | | | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Paulo Gustavo Kotze
- Health Sciences Postgraduate Program, Pontificia Universidade Católica do Paraná [PUCPR], Curitiba, Brazil
| | - Gaetano Luglio
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Christian Maaser
- Outpatients Department of Gastroenterology, University Teaching Hospital Lueneburg, Lueneberg, Germany
| | - Gordon Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK
- Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Nurulamin Noor
- Department of Medicine, University of Cambridge, School of Clinical Medicine, Cambridge, UK
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Georgios Peros
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | | | - Giuseppe Sica
- Department of Surgery, Università Tor Vergata, Roma, Italy
| | - Rotem Sigall-Boneh
- Pediatric Gastroenterology and Nutrition Unit, E. Wolfson Medical Center, Holon, Israel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Henit Yanai
- IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva; Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Pär Myrelid
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Michel Adamina
- Department of Surgery, Cantonal Hospital of Fribourg & Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| |
Collapse
|
44
|
Sigawi T, Israeli A, Ilan Y. Harnessing Variability Signatures and Biological Noise May Enhance Immunotherapies' Efficacy and Act as Novel Biomarkers for Diagnosing and Monitoring Immune-Associated Disorders. Immunotargets Ther 2024; 13:525-539. [PMID: 39431244 PMCID: PMC11488351 DOI: 10.2147/itt.s477841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/27/2024] [Indexed: 10/22/2024] Open
Abstract
Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments.
Collapse
Affiliation(s)
- Tal Sigawi
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| | - Adir Israeli
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| |
Collapse
|
45
|
Little RD, Swaine A, Reynolds R, Gibson DJ, Barrau M, D'Errico F, Hampal R, Sparrow MP, Roblin X, Irving PM, Ward MG. Adalimumab Drug Levels at Secondary Loss of Response Do Not Predict Response to Dose-intensification in Crohn's Disease: A Retrospective, International Multicenter Study. Inflamm Bowel Dis 2024; 30:1714-1723. [PMID: 37951220 DOI: 10.1093/ibd/izad248] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Indexed: 11/13/2023]
Abstract
BACKGROUND The exposure-response relationship is less established for adalimumab (ADA) compared with infliximab in inflammatory bowel disease (IBD). Evidence supporting therapeutic drug monitoring post dose-intensification of ADA is limited. We aimed to explore the association between ADA drug levels and Crohn's disease (CD) activity at loss of response, and at 6 and 12 months post dose-intensification. METHODS We performed a retrospective study of adult patients with CD receiving dose-intensified weekly ADA following secondary loss of response at 3 tertiary centers across 5 years. ADA trough levels were analyzed using a drug-sensitive enzyme-linked immunosorbent assay at loss of response, and 6 and 12 months after dose-intensification. Rates of clinical remission, objective remission (C-reactive protein <5 mg/L, fecal calprotectin <150 µg/g, or absence of inflammation at endoscopy or imaging), and ADA failure were investigated. RESULTS A total of 131 CD patients were included, with a median disease duration of 9 (interquartile range, 4-17) years. 51% were biologic exposed prior to ADA and 50% received concomitant immunomodulators. Baseline drug levels measured at secondary loss of response did not discriminate between subsequent responders and non-responders at either 6 or 12 months post dose-intensification. However, both higher drug levels at 6 and 12 months and a higher increment from baseline were associated with improved outcomes. On receiver-operating characteristic analyses, post-escalation ADA drug levels >10.7 µg/mL (area under the receiver-operating characteristic curve [AUROC], 0.66; P = .013) and >10.9 µg/mL (AUROC, 0.67; P = .032) were associated with objective remission at 6 and 12 months, respectively. CONCLUSIONS Drug levels following dose-intensification rather than at the time of secondary loss of response were associated with subsequent CD remission.
Collapse
Affiliation(s)
- Robert D Little
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| | - Adrian Swaine
- Department of Gastroenterology, Redcliffe Hospital, Redcliffe, Australia
| | - Rebecca Reynolds
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - David J Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| | - Mathilde Barrau
- Gastro-entérologie et Hépatologie, Centre Hospitalier Universitaire de Saint-Étienne, Saint-Étienne, France
| | - Francesca D'Errico
- Department of Gastroenterology and Endoscopy, Miulli Hospital, Acquaviva delle Fonti, Italy
| | - Rumneek Hampal
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| | - Xavier Roblin
- Gastro-entérologie et Hépatologie, Centre Hospitalier Universitaire de Saint-Étienne, Saint-Étienne, France
| | - Peter M Irving
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Mark G Ward
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| |
Collapse
|
46
|
Coelho T, Cheng G, Vazquez Lopez F, Ashton JJ, Beattie RM, Ennis S. Reply: Predicting Adverse Events to Thiopurines in IBD: Are We a Step Closer? Inflamm Bowel Dis 2024; 30:1928-1930. [PMID: 39011772 DOI: 10.1093/ibd/izae130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Affiliation(s)
- Tracy Coelho
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Guo Cheng
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Fernando Vazquez Lopez
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - James J Ashton
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| | - Robert M Beattie
- Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, United Kingdom
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, United Kingdom
| |
Collapse
|
47
|
Lowell JA, Sharma G, Chua V, Ben-Horin S, Swaminath A, Sultan K. Reactive Immunomodulator Addition to Infliximab Monotherapy Restores Clinical Response in Inflammatory Bowel Disease: A Meta-Analysis. Dig Dis Sci 2024; 69:3920-3931. [PMID: 38877332 DOI: 10.1007/s10620-024-08515-5] [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: 04/22/2024] [Accepted: 05/29/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy. METHODS We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation. RESULTS We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%). CONCLUSIONS These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.
Collapse
Affiliation(s)
- Jeffrey A Lowell
- Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, NY, 11030, USA.
- , 300 Community Drive, Manhasset, NY, 11030, USA.
| | - Garvita Sharma
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, 72916, USA
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Vincent Chua
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | - Arun Swaminath
- Division of Gastroenterology, Lenox Hill Hospital, Northwell Health, New York, NY, 10075, USA
| | - Keith Sultan
- Department of Gastroenterology, Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, NY, 11030, USA
| |
Collapse
|
48
|
Roblin X, Little RD, Mathieu N, Paul S, Nancey S, Barrau M, Sparrow MP. Therapeutic drug monitoring in inflammatory bowel disease: recent developments. Expert Rev Gastroenterol Hepatol 2024; 18:575-586. [PMID: 39382556 DOI: 10.1080/17474124.2024.2409300] [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: 08/05/2024] [Revised: 09/03/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024]
Abstract
INTRODUCTION Therapeutic Drug Monitoring (TDM) has an important role in the management of inflammatory bowel disease (IBD) patients on infliximab (IFX) or adalimumab and is recommended in IBD patients presenting a loss of response under anti TNF agent. But, TDM was not recommended for others biotherapies. AREAS COVERED Analyzing all publications about TDM and biologics in IBD patients, we reported the major results for each biotherapy. EXPERT OPINION Emerging data suggest that TDM will probably be similarly useful forIFX SC. In contrast, there is no demonstrated clinical benefit to the use of TDM with golimumab. For vedolizumab results for the use of both reactive and proactive TDM are discordant. For ustekinumab, data supports the existence of an exposure response relationship, albeit of a lesser magnitude than with anti-TNF agents. Finally, recent data from small case series suggests that TDM could be valuable in optimizing anti-IL23 agents, particularly risankizumab, but this requires further clarification. Consistent with the new concept of 'proactive' strategy, recent data support the utility of dashboard-driven model informed precision dosing (MIDP) of anti-TNF agents, in particular infliximab. Dashboards are software systems using Bayesian population pharmacokinetic modelling to individualize recommendations for target drug levels.
Collapse
Affiliation(s)
- Xavier Roblin
- Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
- IBD Private Institute Echirolles, Echirolles, France
| | - Robert D Little
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| | | | - Stephane Paul
- Immunology, University Hospital of Saint Etienne, Saint Etienne, France
| | | | - Mathide Barrau
- Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| |
Collapse
|
49
|
Ali S, Pasternak B, Moses J, Suskind DL, Samson C, Kaplan J, Creps J, Manning L, Baker M, Singer D, Patel P, Trombler B, Anandakrishnan A, Khorrami C, Feldman M, McGoldrick M, Adler J. Characterization of Biologic Discontinuation Among Pediatric Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2024; 22:2075-2083.e1. [PMID: 38723980 DOI: 10.1016/j.cgh.2024.03.043] [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: 09/15/2023] [Revised: 03/26/2024] [Accepted: 03/27/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND & AIMS Biologic therapies may effectively treat Crohn's disease (CD), and pediatric patients who discontinue multiple biologics risk exhausting treatment options. The frequency and context of biologic discontinuation have not been well-characterized. We aimed to determine patterns of biologic use, discontinuation, and evaluation in pediatric patients with CD. METHODS Pediatric patients with CD at 7 U.S. centers (2010-2020) were identified. Prospective ImproveCareNow registry data were supplemented with medical record abstraction. Biologics included monoclonal antibody and small molecule medications. Therapeutic drug monitoring (TDM) was considered induction if <14 weeks after biologic start, proactive if later during quiescent disease, and reactive during active disease. RESULTS Of 823 patients included (median age, 13.0 years; 40% female), 86% started biologics (78% infliximab, 21% adalimumab, <1% others). Twenty-six percent used concomitant immunomodulators for ≥12 months. Most (85%) measured TDM including 47% induction, 69% proactive, and 24% reactive. Twenty-nine percent discontinued their first biologic after median 793 days because of inefficacy (34%), anti-drug antibodies (8%), adverse events (8%), or non-adherence (12%). If inefficacy, 86% underwent pre-discontinuation evaluation. If infliximab or adalimumab inefficacy and TDM was done, 62% had levels <10 μg/mL. Proactive TDM and concomitant immunomodulators were associated with 60% and 32% reduced biologic discontinuation. CONCLUSIONS Most children with CD are treated with biologics; 25%-37% discontinue biologics, resulting in 1 in 12 using >2 biologics during pediatric care. Half of patients discontinued biologics without trial of high-dose therapy and 14% without any evaluation. Concomitant immunomodulator use and proactive TDM decreased risk of biologic discontinuation. Strategies are needed to preserve biologic efficacy and prevent biologic discontinuation.
Collapse
Affiliation(s)
- Sabina Ali
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSF Benioff Children's Hospital, Oakland, California
| | - Brad Pasternak
- Pediatric Gastroenterology, Phoenix Children's Hospital, Phoenix, Arizona
| | - Jonathan Moses
- Division of Gastroenterology, Hepatology, and Nutrition, UH Rainbow Babies & Children's, Cleveland, Ohio
| | - David L Suskind
- Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, Washington
| | - Charles Samson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Jess Kaplan
- Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, Massachusetts
| | - Jana Creps
- Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - Lauren Manning
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, Michigan
| | - Michaella Baker
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, Michigan
| | - Dianne Singer
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, Michigan
| | - Perseus Patel
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSF Benioff Children's Hospital, Oakland, California
| | - Becca Trombler
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSF Benioff Children's Hospital, San Francisco, California
| | | | - Camila Khorrami
- Division of Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, Washington
| | - Maya Feldman
- Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, Massachusetts
| | - Molly McGoldrick
- Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, Massachusetts
| | - Jeremy Adler
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, Michigan; Division of Pediatric Gastroenterology, Michigan Medicine, Ann Arbor, Michigan.
| |
Collapse
|
50
|
Husman J, Černá K, Matthes K, Gilger M, Arsova M, Schmidt A, Winzer N, Brosch AM, Brinkmann F, Hampe J, Zeissig S, Lukáš M, Schmelz R. Subcutaneous infliximab in Crohn's disease patients with previous immunogenic failure of intravenous infliximab. Int J Colorectal Dis 2024; 39:151. [PMID: 39317813 PMCID: PMC11422436 DOI: 10.1007/s00384-024-04727-3] [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] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE Immunogenicity is a major reason for secondary loss of response to infliximab (IFX). Recent work suggested potentially lower immunogenicity of subcutaneous (SC) compared to intravenous (IV) IFX. However, it is unknown whether re-exposure to IFX SC after secondary loss of response and immunogenicity to its intravenous formulation is safe and effective. METHODS In a retrospective cohort study conducted at two medical centers, patients with clinically (Harvey-Bradshaw Index ≥ 5) and/or biochemically (fecal calprotectin > 250 µg/g) active Crohn's disease (CD) and previous immunogenic failure of IFX IV underwent exposure to IFX SC. Harvey-Bradshaw Index, fecal calprotectin, IFX serum concentration, and anti-drug antibodies were assessed until month 12. RESULTS Twenty CD patients were included. The majority of patients (90%) had previous treatment with three or more biologics. Fifteen (75%) and ten (50%) of 20 patients continued IFX SC treatment until months 6 and 12, respectively. No immediate hypersensitivity reactions were observed. Two patients discontinued IFX SC treatment because of delayed hypersensitivity at week 2 and week 4. IFX serum concentrations increased from baseline to month 12, while anti-drug antibody levels decreased. Combined clinical and biochemical remission at month 12 was observed in seven of 20 patients (35%). CONCLUSION Subcutaneous infliximab treatment of Crohn's disease patients with previous immunogenic failure of intravenous infliximab was well tolerated and effective in a cohort of patients with refractory Crohn's disease.
Collapse
Affiliation(s)
- Julia Husman
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Karin Černá
- Clinical and Research Center for Inflammatory Bowel Disease ISCARE and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Katja Matthes
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Maximilian Gilger
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Maia Arsova
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Alexandra Schmidt
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Nadia Winzer
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Anna-Magdalena Brosch
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Franz Brinkmann
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Jochen Hampe
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Sebastian Zeissig
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU), Dresden, Germany
- Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Milan Lukáš
- Clinical and Research Center for Inflammatory Bowel Disease ISCARE and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Renate Schmelz
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany.
| |
Collapse
|