Dose Effect Relationship of MTX and IBD
Condition: Inflammatory Bowel Diseases; Liver Fibroses; Methotrexate
MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases; Liver Cirrhosis; Fibrosis
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Ultrasound Elastography
Intervention type(s): Diagnostic Test
Intervention description(s): 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.
Observational model: Cohort
Time perspective: Prospective
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.
      
Keywords: MTX; IBD; US Elastography; Liver Fibrosis