Dose Effect Relationship of MTX and IBD

July 16, 2018 updated by: Children's Mercy Hospital Kansas City

Dose Effect Relationship of Methotrexate and Hepatic Fibrosis in Patients With Inflammatory Bowel Disease

Currently there are no guidelines for monitoring hepatic fibrosis associated with long term MTX use. Routine liver biopsies are not being done as a part of surveillance due to potential complications like bleeding and pneumothorax. Non-invasive markers like gammaglamyltransferase (GGTP), Alkaline Phosphatase (AlkPhos), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are deranged at a late stage and may not be helpful in detecting early fibrosis. The current study will utilize a sensitive, but noninvasive, test to evaluate for hepatic fibrosis. We are attempting to screen for early detection of fibrosis due to MTX before it progresses to irreversible cirrhosis and end-stage liver disease. Based on the results of this pilot study, ultrasound elastography could be used to prospectively study a larger population to establish guidelines for monitoring safety and hepatic complications with MTX. The influence of other co-morbid factors like obesity, alcohol ingestion and smoking is critical to identifying high risk patients who may require closer monitoring. We follow close to 550 patients with IBD. If we presume that at least 20% patients are currently receiving methotrexate, we will be able to recruit enough patients for this pilot study.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Inflammatory bowel disease is a chronic, relapsing and remitting, inflammatory disorder of the GI tract. The mainstay of medical therapy is comprised of 5-aminosalicylates, corticosteroids, immunomodulators such as mercaptopurine and MTX, and biologics such as infliximab and adalimumab.

Mercaptopurine historically had been the immunomodulator of choice for disease maintenance and as an adjuvant to biologic therapy to prevent antibody formation.

However in 2008 the FDA communicated an increase incidence of a lethal blood cancer, hepatosplenic T-cell lymphoma, in adolescent males taking mercaptopurine along with Infliximab. In addition there is a known four-fold increase in the risk of lymphoma in patients treated with mercaptopurine while the risk is not significantly increased with MTX use. Due to these reasons there has been a shift amongst pediatric gastroenterologists to starting children with newly diagnosed IBD on MTX as a first line immunomodulator and/or as an adjuvant to biologic therapy. Given the chronic nature of this disease, children are more likely to be on long term MTX therapy. There is paucity of data for evaluation and monitoring of hepatic fibrosis associated with prolonged methotrexate usage in patients with IBD. The influence of co-morbid factors like obesity, alcohol intake and smoking are also not well understood. The primary purpose of this pilot study is to assess for hepatic fibrosis using shear wave elastography in patients on methotrexate in relation to the cumulative dose they have received. .

MTX is a folic acid antagonist, which has been used as a mainstay of therapy in other chronic inflammatory diseases such as rheumatoid arthritis and psoriatic arthritis. Known side effects from the medication are nausea, leukopenia and hepatotoxicity. In addition, patients with refractory psoriasis on MTX therapy are reported to develop hepatic fibrosis in a cumulative dose dependent fashion. Currently the gold standard of assessment is a liver biopsy, as serological biomarkers have proven to correlate poorly in early stages of fibrosis. Liver biopsy is not only an invasive test but could lead to serious complications such as pneumothorax and intra-peritoneal bleeding.

As standard of care our pediatric patients with IBD on MTX therapy are screened quarterly with serological biomarkers such as complete blood counts, albumin and liver function tests to evaluate for these side effects. As previously stated, the dilemma arises in that the derangement of these lab tests poorly correlate with early stages of fibrosis and it is likely that by the time they are elevated the patient already has experienced irreversible liver damage. In fact in an adult study by Te et al in 2000 reported that patients with IBD on MTX show poor correlation of liver function tests and histological findings on liver biopsy. Therefore they concluded that following the same surveillance guidelines in IBD patients on MTX as those with psoriasis on MTX is not warranted as risks of the procedure outweigh the benefits of biopsy. Pediatric patients with a lifelong diagnosis of IBD and a life expectancy of 80 years can reach a considerably higher cumulative MTX dose over their lifetime and may need non-invasive monitoring for liver damage and fibrosis.

Ultrasound elastography is a new, noninvasive technique that can assess the stiffness of the liver by the evaluation of how sound waves propagate through the liver parenchyma. It can evaluate multiple areas of the liver in contrast to liver biopsy that only can sample a small area of tissue. Sampling of multiple areas of the liver is helpful in heterogeneous distribution of liver disease. Several recent studies have demonstrated the superiority of shear wave elastography over other older ultrasound based methods. A recent study also demonstrated reliability of detecting hepatic fibrosis in children using shearwave elastography and correlating with simultaneously obtained liver biopsies (7) Shear wave ultrasound elastography is a quantitative subset of ultrasound elastography that has good reproducibility and has good sensitivity/specificity for assessing for severe fibrosis and cirrhosis. A recent report by Tae Yeob Kim et al (demonstrated hepatic fibrosis in 5% patients on long term methotrexate for rheumatoid arthritis which was associated with high body mass index rather than cumulative methotrexate dose).(8) There are no similar studies in children or adults with IBD.

2. RATIONALE Currently there are no guidelines for monitoring hepatic fibrosis associated with long term MTX use. Routine liver biopsies are not being done as a part of surveillance due to potential complications like bleeding and pneumothorax. Non-invasive markers like gammaglamyltransferase (GGTP), Alkaline Phosphatase (AlkPhos), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are deranged at a late stage and may not be helpful in detecting early fibrosis. The current study will utilize a sensitive, but noninvasive, test to evaluate for hepatic fibrosis. We are attempting to screen for early detection of fibrosis due to MTX before it progresses to irreversible cirrhosis and end-stage liver disease. Based on the results of this pilot study, ultrasound elastography could be used to prospectively study a larger population to establish guidelines for monitoring safety and hepatic complications with MTX. The influence of other co-morbid factors like obesity, alcohol ingestion and smoking is critical to identifying high risk patients who may require closer monitoring. We follow close to 550 patients with IBD. If we presume that at least 20% patients are currently receiving methotrexate, we will be able to recruit enough patients for this pilot study.

STUDY DESIGN

This is a single site prospective cross-sectional pilot study that will aim to enroll IBD patients who have different cumulative dose exposures to MTX. Each patient who consents will undergo an ultrasound elastography exam. We will aim to enroll an equal number of patients in four categories (25 each) based on lifetime cumulative MTX dose:

Category Lifetime cumulative MTX dose (g) 0 (Control Group) No MTX, but DX of IBD

  1. 0-1.5
  2. 1.5-3
  3. >3

3. TARGET STUDY POPULATION SPECIFICS Inclusion Criteria

• Patients age 2-22 years of age who have a diagnosis of IBD and consent to our study.

Exclusion Criteria

  • Patient is unable to tolerate an ultrasound elastography examination.
  • Target enrollment for the MTX dose category in which the patient fits has been completed.

  • Any preexisting liver disease

    4. DATA COLLECTION Data Collection Procedures Candidates for the study will be identified by the Gastroenterology service or self-refer in response to advertisements and will be consented by one of the members of the research team. Consented subjects will be scheduled for research ultrasound elastography examination at CMH. Dr. Chan, Pediatric Radiologist and Co-Investigator, will review the ultrasound elastography images for shear wave velocity. Demographic and clinical variables will be collected from the chart at the time of enrollment and ultrasound elastography examination.

Study Type

Observational

Enrollment (Actual)

64

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 22 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients ages 2-22 whom have a diagnosis of IBD can participate in our study. We will recruit a total of 100 subjects; 25 control subjects and 75 subjects whom are taking Methotrexate for their IBD.

Description

Inclusion Criteria:

  • Patients age 2-22 years of age who have a diagnosis of IBD and consent to our study.

Exclusion Criteria:

  • Patient is unable to tolerate an ultrasound elastography examination.
  • Target enrollment for the MTX dose category in which the patient fits has been completed.
  • Any preexisting liver disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
US Elastography
All subjects will undergo one ultrasound elastography examination after consent.
Diagnostic test: Ultrasound Elastography
Ultrasound elastography is a new, noninvasive technique that can assess the stiffness of the liver by the evaluation of how sound waves propagate through the liver parenchyma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Objective - correlation between velocities of shear wave elastography and cumulative dose of Methotrexate (MTX) in patients with Inflammatory Bowel Disease (IBD).
Time Frame: 2/1/2017-10/31/2017
To evaluate the correlation between velocities of shear wave elastography and cumulative dose of Methotrexate (MTX) in patients with Inflammatory Bowel Disease (IBD).
2/1/2017-10/31/2017

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary Objective - correlate hepatic enzymes elevation and ultrasound elastography velocities
Time Frame: 2/1/2017-10/31/2017
To correlate hepatic enzymes elevation and ultrasound elastography velocities.
2/1/2017-10/31/2017
Third Objective - changes in shear wave velocity
Time Frame: 2/1/2017-10/31/2017
To assess if changes in shear wave velocity due to Methotrexate are influenced by other risk factors like obesity, alcohol ingestion, smoking
2/1/2017-10/31/2017
Fourth Objective - correlate ultrasound elastography findings with fibrosis markers
Time Frame: 2/1/2017-10/31/2017
To correlate ultrasound elastography findings with fibrosis markers: AST/ALT ratio (AST (U/L0/ALT (U/L); AST/platelet ratio index (AST/upper limit of normal)/Platelet count (109/L) X 100
2/1/2017-10/31/2017

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Mercy Hospital Kansas City

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2017

Primary Completion (Actual)

May 31, 2018

Study Completion (Actual)

May 31, 2018

Study Registration Dates

First Submitted

April 26, 2017

First Submitted That Met QC Criteria

May 21, 2018

First Posted (Actual)

May 22, 2018

Study Record Updates

Last Update Posted (Actual)

July 17, 2018

Last Update Submitted That Met QC Criteria

July 16, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16040304

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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