Biological Therapy: The Assess of Clinical Efficacy and Safety in Immune Mediated Inflammatory Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 25925

Special Issue Editor


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Guest Editor
Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Interests: therapeutic drug monitoring; anti-TNF therapy; biologics; inflammatory bowel disease; immunogenicity
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Special Issue Information

Dear Colleagues,

Anti-tumor necrosis factor (TNF) therapy—namely, infliximab, adalimumab, certolizumab pegol, and golimumab—is very effective for treating moderate-to-severe inflammatory bowel disease (IBD), with a good safety profile. Anti-TNF therapy has also been used to treat pouchitis following ileal pouch-anal anastomosis after restorative proctocolectomy and to prevent post-operative recurrence following ileocolonic resection for Crohn’s disease with good results. Nevertheless, up to one-third of patients show no clinical benefit following induction and up to 50% lose response over time. Both these unwanted outcomes can be largely explained by inadequate drug concentrations and frequently by the development of anti-drug antibodies—so-called immunogenicity. Reactive therapeutic drug monitoring (TDM) has rationalized the management of loss of response, and is more cost-effective than empirical treatment optimization based only on symptoms. Recent data suggest that proactive TDM and dosing to a therapeutic drug concentration in patients in clinical remission is associated with improved long-term outcomes. The aim of this Special Issue is to highlight recent advances in the context of efficacy and safety of anti-TNF therapy in IBD.

Prof. Dr. Konstantinos Papamichael
Guest Editor

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Keywords

  • Ulcerative colitis
  • Crohn's disease
  • Infliximab
  • Adalimumab
  • Certolizumab pegol
  • Golimumab

Published Papers (7 papers)

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Research

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10 pages, 4308 KiB  
Article
Vedolizumab Serum Trough Concentrations and Response to Dose Escalation in Inflammatory Bowel Disease
by Byron P. Vaughn, Andres J. Yarur, Elliot Graziano, James P. Campbell, Abhik Bhattacharya, Jennifer Y. Lee, Katherine Gheysens, Konstantinos Papamichael, Mark T. Osterman, Adam S. Cheifetz and Raymond K. Cross
J. Clin. Med. 2020, 9(10), 3142; https://doi.org/10.3390/jcm9103142 - 28 Sep 2020
Cited by 19 | Viewed by 3109
Abstract
Serum vedolizumab concentrations are associated with clinical response although, it is unknown if vedolizumab concentrations predict response to dose escalation. The aim of this study was to identify if vedolizumab trough concentrations predicted the response to vedolizumab dose escalation. We assessed a retrospective [...] Read more.
Serum vedolizumab concentrations are associated with clinical response although, it is unknown if vedolizumab concentrations predict response to dose escalation. The aim of this study was to identify if vedolizumab trough concentrations predicted the response to vedolizumab dose escalation. We assessed a retrospective cohort of patients on maintenance vedolizumab dosing at five tertiary care centers with vedolizumab trough concentrations. Multivariate logistic regression was used to control for potential confounders of association of vedolizumab concentration and clinical status. Those who underwent a dose escalation were further examined to assess if vedolizumab trough concentration predicted the subsequent response. One hundred ninety-two patients were included. On multivariate analysis, vedolizumab trough concentration (p = 0.03) and the use of immunomodulator (p = 0.006) were associated with clinical remission. Receiver operator curve analysis identified a cut off of 7.4 μg/mL for clinical remission. Of the fifty-eight patients with dose escalated, 74% of those with a vedolizumab concentration <7.4 μg/mL responded versus 52% of those with a vedolizumab trough concentration ≥7.4 μg/mL (p = 0.08). After adjustment for relevant confounders, the odds ratio for response with vedolizumab concentration <7.4 μg/mL was 3.7 (95% CI, 1.1–13; p = 0.04). Vedolizumab trough concentration are associated with clinical status and can identify individuals likely to respond to dose escalation. However, a substantial portion of patients above the identified cut off still had a positive response. Vedolizumab trough concentration is a potentially helpful factor in determining the need for dose escalation in patients losing response. Full article
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9 pages, 789 KiB  
Article
Time Trends of Crohn’s Disease in Catalonia from 2011 to 2017. Increasing Use of Biologics Correlates with a Reduced Need for Surgery
by Eduard Brunet, Emili Vela, Luigi Melcarne, Montserrat Clèries, Caridad Pontes, Laura Patricia Llovet, Pilar García-Iglesias, Marta Gallach, Albert Villòria, Mercedes Vergara and Xavier Calvet
J. Clin. Med. 2020, 9(9), 2896; https://doi.org/10.3390/jcm9092896 - 8 Sep 2020
Cited by 10 | Viewed by 2424
Abstract
Background and Aims: Data from clinical trials suggest that biological drugs may improve the outcomes in Crohn’s disease (CD) by reducing the need for surgery or hospitalization. The aim of this study is to evaluate the time-trends of the use of biological drugs [...] Read more.
Background and Aims: Data from clinical trials suggest that biological drugs may improve the outcomes in Crohn’s disease (CD) by reducing the need for surgery or hospitalization. The aim of this study is to evaluate the time-trends of the use of biological drugs and other treatments for CD, and its relationship with outcomes in Catalonia. Materials and Methods: All patients with CD included in the Catalan Health Surveillance System (containing data on a population of more than 7.5 million) from 2011 to 2017 were identified. The exposures to different treatments for inflammatory bowel disease were retrieved from electronic invoicing records. Results: Between 2011 and 2017, the use of salicylates, corticosteroids and immunosuppressive treatment fell from 28.8% to 17.1%, 15.8% to 13.7%, and 32.9% to 29.6%, respectively (p < 0.001). Biological treatment use rose from 15.0% to 18.7% (p < 0.001). Ostomy rates per 1000 patients/year fell from 13.2 in 2011 to 9.8 in 2017 (p = 0.003), and surgical resection rates from 24.1 to 18.0 (p < 0.001). The rate of CD-related hospitalizations per 1000 patients/year also fell, from 92.7 to 72.2 (p < 0.001). Conclusions: Biological drug use rose from 15.0% to 18.7% between 2011 and 2017. During this period, we observed an improvement in the outcomes of CD patients. Full article
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9 pages, 2097 KiB  
Article
Clinical Impact of Corrections to Infliximab and Adalimumab Monitoring Results with the Homogeneous Mobility Shift Assay
by Konstantinos Papamichael, Valerio J. Thomas, Andrea Banty, William T. Clarke, Katharine A. Germansky, Sarah N. Flier, Joseph D. Feuerstein, Gil Y. Melmed and Adam S. Cheifetz
J. Clin. Med. 2020, 9(9), 2840; https://doi.org/10.3390/jcm9092840 - 2 Sep 2020
Cited by 1 | Viewed by 1693
Abstract
An upward drift for both infliximab and adalimumab concentrations measured by the homogenous mobility shift assay (HMSA) was previously reported. We aimed to investigate the impact of this drift on clinical care of patients with inflammatory bowel disease. This was a retrospective, multicenter [...] Read more.
An upward drift for both infliximab and adalimumab concentrations measured by the homogenous mobility shift assay (HMSA) was previously reported. We aimed to investigate the impact of this drift on clinical care of patients with inflammatory bowel disease. This was a retrospective, multicenter study. Providers reviewed the individual patient data and drug concentrations before and after the laboratory corrections and then documented whether a different clinical decision would have been made had the corrected drug concentration been originally reported. A multivariable Cox proportional hazards regression analysis was performed to investigate the association of a documented treatment change with treatment failure, defined as drug discontinuation for primary nonresponse, loss of response, or serious adverse event, adjusting for confounding factors. The study population consisted of 479 patients (infliximab, n = 219; adalimumab, n = 260). Upon review, 14.9% (71/479) patients would have had a different treatment decision made had the corrected drug concentration been initially reported. After a median follow-up of 10.6 months, 25.7% of patients (123/479) had treatment failure. A theoretical different clinical decision based on the corrected drug concentrations was not associated with treatment failure (adjusted hazard ratio (HR): 1.452; 95% confidence interval (CI): 0.805–2.618; p = 0.216), which was consistent for both infliximab (adjusted HR: 1.977; 95% CI: 0.695–5.627; p = 0.201) and adalimumab (adjusted HR: 1.484; 95% CI: 0.721–3.054; p = 0.284). The drift in infliximab and adalimumab concentrations in the HMSA assay affected treatment decisions in 15% of cases. However, this discrepancy was not associated with a higher cumulative probability for treatment failure. Full article
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Review

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15 pages, 303 KiB  
Review
Update on TDM (Therapeutic Drug Monitoring) with Ustekinumab, Vedolizumab and Tofacitinib in Inflammatory Bowel Disease
by Sophie Restellini and Waqqas Afif
J. Clin. Med. 2021, 10(6), 1242; https://doi.org/10.3390/jcm10061242 - 17 Mar 2021
Cited by 26 | Viewed by 5230
Abstract
The goal of therapeutic drug monitoring (TDM) is to optimize anti-TNF (tumor necrosis factor) biologic treatment in patients with inflammatory bowel disease (IBD). Although commercial assays are readily available for both ustekinumab and vedolizumab, the use of TDM with these newer biologic medications [...] Read more.
The goal of therapeutic drug monitoring (TDM) is to optimize anti-TNF (tumor necrosis factor) biologic treatment in patients with inflammatory bowel disease (IBD). Although commercial assays are readily available for both ustekinumab and vedolizumab, the use of TDM with these newer biologic medications is at its infancy. The clinical utility of TDM with non-anti-TNF mechanisms of action is not clear. This review summarizes the latest available data on the pharmacokinetics of newer biologic and oral small molecules and highlights the threshold concentrations that have been associated with improved outcomes in IBD patients. Full article
15 pages, 1082 KiB  
Review
Cutaneous Manifestations in Biological-Treated Inflammatory Bowel Disease Patients: A Narrative Review
by Jo L. W. Lambert, Sofie De Schepper and Reinhart Speeckaert
J. Clin. Med. 2021, 10(5), 1040; https://doi.org/10.3390/jcm10051040 - 3 Mar 2021
Cited by 12 | Viewed by 7730
Abstract
The biologic era has greatly improved the treatment of Crohn’s disease and ulcerative colitis. Biologics can however induce a wide variety of skin eruptions, especially those targeting the TNF-α and Th17 pathway. These include infusion reactions, eczema, psoriasis, lupus, alopecia areata, vitiligo, lichenoid [...] Read more.
The biologic era has greatly improved the treatment of Crohn’s disease and ulcerative colitis. Biologics can however induce a wide variety of skin eruptions, especially those targeting the TNF-α and Th17 pathway. These include infusion reactions, eczema, psoriasis, lupus, alopecia areata, vitiligo, lichenoid reactions, granulomatous disorders, vasculitis, skin cancer, and cutaneous infections. It is important to recognize these conditions as treatment-induced adverse reactions and adapt the treatment strategy accordingly. Some conditions can be treated topically while others require cessation or switch of the biological therapy. TNF-α antagonists have the highest rate adverse skin eruptions followed by ustekinumab and anti-integrin receptor blockers. In this review, we provide an overview of the most common skin eruptions which can be encountered in clinical practice when treating IBD (Inflammatory bowel disease) patients and propose a therapeutic approach for each condition. Full article
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20 pages, 691 KiB  
Review
Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases
by Giuseppe Privitera, Daniela Pugliese, Gian Ludovico Rapaccini, Antonio Gasbarrini, Alessandro Armuzzi and Luisa Guidi
J. Clin. Med. 2021, 10(4), 853; https://doi.org/10.3390/jcm10040853 - 19 Feb 2021
Cited by 22 | Viewed by 3186
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, [...] Read more.
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD. Full article
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14 pages, 435 KiB  
Review
Exploring the Relationship between Biologics and Postoperative Surgical Morbidity in Ulcerative Colitis: A Review
by Abel Botelho Quaresma, Fernanda da Silva Barbosa Baraúna, Fábio Vieira Teixeira, Rogério Saad-Hossne and Paulo Gustavo Kotze
J. Clin. Med. 2021, 10(4), 710; https://doi.org/10.3390/jcm10040710 - 11 Feb 2021
Cited by 6 | Viewed by 1915
Abstract
Background: With the paradigm shift related to the overspread use of biological agents in the treatment of inflammatory bowel diseases (IBD), several questions emerged from the surgical perspective. Whether the use of biologicals would be associated with higher rates of postoperative complications in [...] Read more.
Background: With the paradigm shift related to the overspread use of biological agents in the treatment of inflammatory bowel diseases (IBD), several questions emerged from the surgical perspective. Whether the use of biologicals would be associated with higher rates of postoperative complications in ulcerative colitis (UC) patients still remains controversial. Aims: We aimed to analyze the literature, searching for studies that correlated postoperative complications and preoperative exposure to biologics in UC patients, and synthesize these data qualitatively in order to check the possible impact of biologics on postoperative surgical morbidity in this population. Methods: Included studies were identified by electronic search in the PUBMED database according to the PRISMA (Preferred Items of Reports for Systematic Reviews and Meta-Analysis) guidelines. The quality and bias assessments were performed by MINORS (methodological index for non-randomized studies) criteria for non-randomized studies. Results: 608 studies were initially identified, 22 of which were selected for qualitative evaluation. From those, 19 studies (17 retrospective and two prospective) included preoperative anti-TNF. Seven described an increased risk of postoperative complications, and 12 showed no significant increase postoperative morbidity. Only three studies included surgical UC patients with previous use of vedolizumab, two retrospective and one prospective, all with no significant correlation between the drug and an increase in postoperative complication rates. Conclusions: Despite conflicting results, most studies have not shown increased complication rates after abdominal surgical procedures in patients with UC with preoperative exposure to biologics. Further prospective studies are needed to better establish the impact of preoperative biologics and surgical complications in UC. Full article
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