Individualizing Anti-TNF Therapy in Patients With Inflammatory Bowel Disease

Individualizing Anti-TNF Therapy in Patients With Inflammatory Bowel Disease: Pre-Treatment Prediction of Immunogenicity and Response. A Prospective Observational Study.

This observational study aims to identify genes that may affect how patients with inflammatory bowel disease respond to anti-TNF treatment and why some patients lose response to treatment over time. The study will examine whether genetic markers can help predict which patients are more likely to respond to anti-TNF therapy.

Participants who have not previously received anti-TNF treatment and are about to start advanced therapy will provide a blood sample to test for the genetic markers. Participants will also undergo regular assessments of current treatment, disease activity, and inflammatory markers during follow-up.

Study Overview

• Status: Recruiting
• Conditions: Crohn Disease (CD); Ulcerative Colitis (UC); IBD (Inflammatory Bowel Disease)
• Intervention / Treatment: Other: This is an observational study with no intervention. Patients will receive anti- TNF therapy as part of their standard care

Detailed Description

The introduction of anti-TNF therapy was a pivotal milestone in the treatment of inflammatory bowel diseases (IBD). Since then, additional advanced therapies with novel mechanisms of action have been introduced. The plethora of biologics and small molecule drugs increases the ability of IBD patients to achieve therapeutic goals, such as clinical, endoscopic and mucosal healing. However, primary non-response and loss of response remain a challenge and are linked to increase risks related to ongoing inflammation and disease progression.

Predicting the response rates of individual patients to therapy is the goal of a large body of research, linked to clinical characteristics, genetics, microbiome composition and pharmacokinetics. Two promising research topics are Triggering Receptor Expressed in Myeloid cells 1 (TREM1) and HLA-DQA1*05.

TREM1 is a receptor expressed on innate immune cells, known to amplify inflammatory signals triggered by Toll-like receptors, thus contributing to the pathophysiology of acute and chronic inflammatory conditions. Increased protein and mRNA levels of TREM1 in whole blood and colonic biopsies are associated with clinical and endoscopic non-response to anti-TNF. The suggested best cut-off point is 3.346 folds increase in mRNA expression in whole blood samples, with a specificity of 91.3% and sensitivity of 58.1%.

HLA class II gene HLA-DQA1 is expressed by antigen presenting cells and encodes the α-chain of the HLA-DQ heterodimer that forms part of the antigen-binding site where epitopes are presented to T-helper cells. Carriage of HLA-DQA1*05 allele confers a 2-fold risk of immunogenicity to anti-TNF therapy. This risk was mitigated using a concomitant immunomodulator.

Our goal is to evaluate the predictive power of these tests separately in a prospective observational study, and assess whether combining the tests' outcomes prior to initiation of anti-TNF therapy improve therapy outcomes, including efficacy and durability.

The aims of this study are to assess the effectiveness of each test, and the combined tests for TREM1 and HLA-DQA1*05 to improve clinical and endoscopic response and remission rates, in patients with IBD starting anti-TNF therapy. The study will also assess the effectiveness of each test, and the combined tests for TREM1 and HLA-DQA1*05 in improving anti-TNF treatment durability and immunogenicity.

Participants will provide blood samples prior to treatment initiation for the assessment of HLA-DQA1*05 using quantitative real-time polymerase chain reaction (qRT-PCR) and TREM1 levels using an enzyme-linked immunosorbent assay (ELISA).

Drug and antibody levels will be measured at weeks 8, 24, and 52. Participants will also undergo periodic evaluations of their medical therapy and clinical disease activity throughout the study period.

Endoscopic disease activity (endoscopic MAYO score [eMAYO] for UC, and simple endoscopic score [SES-CD] for CD) will be evaluated with endoscopy 6-12 months after starting therapy, if performed as standard of care by the treating physician's discretion.

Statistical analysis Continuous variables will be presented as mean ± standard deviation for normal distribution and median with interquartile range for non-normal distribution. Nominal variables will be presented as proportions. Pearson correlation coefficient will be calculated to find association between HLA-DQA1*05 and anti-TNF immunogenicity, and between TREM1 expression and anti-TNF response rates. ROC curve with Youden index will be used to calculated area under the curve and optimal tests results predicting immunogenicity and response to therapy. Chi-Square test will be used to test the association between nominal variables. Comparison of continued variables groups will be performed by the independent samples t-test for variables which distribute normally, and by the Mann-Whitney test for variables which did not distribute normally. Normality will be tested graphically and using the Shapiro Wilk's test. Comparison of immunogenicity and response to therapy between study visits, and evaluation of the overtime trends in these parameters, in accordance with HLA-DQA1*05 and TREM1 tests results, will be performed by using the linear mixed model analysis (three or more visits) and by the paired sample T test (two visits). Statistical significance was set at P ≤ 0.05. All statistical analyses will be performed using R-4.3.2 for Windows.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Rony Izhar, PhD; Phone Number: +97237772613; Email: ronyi@tlvmc.gov.il
• Study Contact Backup: Name: Ayal Hirsch, MD; Phone Number: +972535289492; Email: ayalh@tlvmc.gov.il

Study Locations

• Israel
  • Tel Aviv, Israel
    • Recruiting
    • Dep. of Gastroenterology, Tel Aviv Sourasky Medical Center
    • Contact: Ayal Hirsch, MD; Phone Number: +972535289492; Email: ayalh@tlvmc.gov.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients followed in the IBD unit in TLVMC starting or switching biologic therapy

Description

Inclusion Criteria:

• Established IBD: Crohn's disease (CD) or ulcerative colitis (UC)
• Anti-TNF naïve
• Clinically active disease (HBI>5 for CD, p-MS≥ 3 for UC)
• Elevated inflammatory indices CRP>10 or fecal calprotectin>250

Exclusion Criteria:

• Unable to provide informed consent
• Anti-TNF experienced
• Unable to complete the study protocol

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
IBD patients; naïve to anti-TNF therapy	Other: This is an observational study with no intervention. Patients will receive anti- TNF therapy as part of their standard care; Patients will receive therapy as part of their standard care according to the standard dose; Other Names: Adalimumab (Humira); Infliximab (Remicade); Certolizumab pegol (Cimzia); Golimumab (Simponi)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of clinical response in UC patients	Defined as decrease from baseline in partial Mayo score (p-MS) of ≥30%, plus a decrease in each sub score of ≥1.	Week 8
Rates of clinical response in UC patients	Defined as decrease from baseline in partial Mayo score (p-MS) of ≥30%, plus a decrease in each sub score of ≥1.	Week 24
Rates of clinical response in UC patients	Defined as decrease from baseline in partial Mayo score (p-MS) of ≥30%, plus a decrease in each sub score of ≥1.	Week 52
Rates of clinical response in CD patients	Defined as decrease of at least 30% in Harvey-Bradshaw index (HBI).	Week 8
Rates of clinical response in CD patients	Defined as decrease of at least 30% in Harvey-Bradshaw index (HBI).	Week 24
Rates of clinical response in CD patients	Defined as decrease of at least 30% in Harvey-Bradshaw index (HBI).	Week 52
Rates of clinical remission for UC	p-MS <3 and no sub score>1	Week 8
Rates of clinical remission for UC	p-MS <3 and no sub score>1	Week 24
Rates of clinical remission for UC	p-MS <3 and no sub score>1	Week 52
Rates of clinical remission for CD	defined as HBI≤4	Week 8
Rates of clinical remission for CD	defined as HBI≤4	Week 24
Rates of clinical remission for CD	defined as HBI≤4	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
c-reactive protein (CRP) levels	Change from baseline in CRP levels	Week 8
CRP levels	Change from baseline in CRP levels	Week 24
CRP levels	Change from baseline in CRP levels	Week 52
Fecal calprotectin levels	Change from baseline in fecal calprotectin levels	Week 8
Fecal calprotectin levels	Change from baseline in fecal calprotectin levels	Week 24
Fecal calprotectin levels	Change from baseline in fecal calprotectin levels	Week 52
Rates of endoscopic response for UC	Endoscopic response defined as Mayo endoscopic sub-score (MES) ≤1	Up to 12 months after initiating treatment
Rates of endoscopic response for CD	Endoscopic response defined as decrease in CDEIS>50%	Up to 12 month after initiation of treatment
Rates of endoscopic remission for UC	defined as MES=0	Up to 12 month after initiation of treatment
Rates of endoscopic remission for CD	defined as CDEIS<6 (CDEIS≤4 for isolated ileitis).	Up to 12 month after initiation of treatment
Immunogenicity	anti-drug antibodies levels	Week 8
Immunogenicity	anti-drug antibodies levels	Week 24
Immunogenicity	anti-drug antibodies levels	Week 52
Drug levels	Serum drug levels	Week 8
Drug levels	Serum drug levels	Week 24
Drug levels	Serum drug levels	Week 52
Therapeutic success	Therapy persistence or discontinuation	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Shmuel Kivity, MD
• Investigators: Principal Investigator: Ayal Hirsch, MD, Tel Aviv Sourasky University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2025
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: May 31, 2026
• First Submitted That Met QC Criteria: June 11, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Anti-TNF; IBD; Response to treatment
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Gastroenteritis; Colitis; Colitis, Ulcerative; Crohn Disease; Inflammatory Bowel Diseases; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Polymers; Macromolecular Substances; Immunoglobulin Fragments; Peptide Fragments; Polyethylene Glycols; Immunoglobulin Fab Fragments; Adalimumab; Infliximab; Certolizumab Pegol; golimumab
• Other Study ID Numbers: 0156-TLV-GN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: At this time, there are no plans for data sharing or external collaborations. If data sharing is pursued in the future; only de-identified participant data will be shared, including demographic information, clinical indices and response to treatment.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No