None listed
Conditions
Brief summary
Low dose oral methotrexate (MTX) is used widely in the treatment of rheumatoid arthritis (RA). The dose individual patients require varies and is largely unpredictable. Differences in dose requirements are at least partially due to differences in the pharmacokinetics of methotrexate. Genetic differences in the enzymes that metabolise MTX may be important. Methotrexate is metabolised to form methotrexate polyglutamates (MTXPGs), which are stored in circulating red blood cells (RBC) and white blood cells. MTXPG concentrations can be measured in these cells. There is evidence that the higher the RBC MTXPG concentration, the greater the likelihood a patient’s arthritis will respond to methotrexate. We wish to investigate MTXPG concentrations and clinical response in patients taking MTX for RA. This will involve studying patients that are starting or stopping MTX, as well as those on a stable dose of MTX. We will investigate the relationship between RBC MTXPG concentrations and clinical response to MTX. Patients who are not responding adequately to oral MTX are often changed to subcutaneous (SC) injections of MTX. In this group we will examine whether there is any improvement in clinical response and the relationship of response to RBC MTXPG concentrations after the change in route of administration. In order to explain individual variations in clinical response to MTX and variations in MTXPG concentrations we will investigate for differences in genes for enzymes or drug transporters that might influence concentrations.
Interventions
Recruitment: Patients seen by the Christchurch Hospital Rheumatology service will be recruited. Patients fulfilling the inclusion/exclusion criteria will be invited to participate.
Treatment of non-responders Patients who are deemed MTX non-responders (DAS>3.2) will have the oral dose of MTX increased to the maximum tolerable dose or 20mg weekly. Lower doses may be used in patients with significant renal impairment at the discretion of the investigator.
If their RA remains active (DAS>3.2) at
Recruitment: Patients seen by the Christchurch Hospital Rheumatology service will be recruited. Patients fulfilling the inclusion/exclusion criteria will be invited to participate. Treatment of non-responders Patients who are deemed MTX non-responders (DAS>3.2) will have the oral dose of MTX increased to the maximum tolerable dose or 20mg weekly. Lower doses may be used in patients with significant renal impairment at the discretion of the investigator. If their RA remains active (DAS>3.2) at the maximum dose the route of MTX administration will be changed to subcutaneous (SC) injection. Patients changed to SC MTX will be seen at weeks 8, 16 and 24 to determine disease activity and side effects to MTX. Red blood cell (RBC) methotrexat polyglutamate (MTXPGs) concentrations will be determined weekly until steady state concentrations are reached then at each follow-up visit. Patients starting or stopping MTX (Pharmacokinetic/clearance studies) Ten patients with RA starting MTX will be recruited. Each patient will be seen at weeks 0, 8, 16 and 24. Disease activity will be assessed as outlined above. Blood samples will be taken weekly to determine RBC MTXPG concentrations until a steady concentration is reached. This is expected to take between 8 to 16 weeks. More or less frequent blood tests may be required depending on the initial data. Ten patients with RA stopping MTX will be recruited. Each patient will be seen once when the MTX is stopped, then at weeks 8, 16 and 24. Blood samples will be taken weekly until concentrations of RBC MTXPGs are undetectable. This is expected to take 8-16 weeks. More or less frequent blood tests may be required depending on the initial data.
Sponsors
Lisa Stamp
Study design
Allocation
Non-randomised trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
I. Patients with RA (ARA ’87 Criteria, (Arnett et al. 1988). II Methotrexate therapy either as monotherapy or combination therapy for at least three months. The dose of methotrexate must be at a stable dose of 5-20 mg/weekly over the preceding four weeks.III Patients whom the treating Rheumatologist wishes to start or stop MTX.IV Able and willing to give written informed consent and to comply with the requirements of the study.
Exclusion criteria
I. A change in dose or introduction of another disease modifying anti-rheumatic drug, nonsteroidal anti-inflammatory agent or oral steroid within the preceding month.II. Intra-articular steroid injections within one month prior to enrolment.III. Evidence of serious uncontrolled chronic concomitant disease.
Outcome results
None listed