This project will compare the efficacy and safety of 2 methods of disease modification in the
treatment of active moderate and severe thyroid orbitopathy. A prospective, randomized,
double-blind, parallel, controlled multidisciplinary clinical trial involving Singapore
National Eye Centre, National University Hospital, Changi General Hospital, Tan Tock Seng
Hospital and University of British Columbia Orbital Services, Singapore Eye Research
Institute, Singapore General Hospital Endocrinology and Radiology Departments and Tan Tock
Seng Hospital Rheumatology Department is planned. The SingHealth-SGH High Field MR Research
Laboratory will be involved in the MR imaging of the trial patients.
Patients who satisfy the inclusion and exclusion criteria will be asked to participate in
this trial. After informed consent (Appendix B) is obtained, each patient will be randomized
into one of two treatment arms: 1) Intravenous high-dose pulsed methylprednisolone (1 gram
infusion over 1 hour per day with a total of 3 doses over 3 days; 4 cycles at 6 weekly
intervals) and oral placebo and 2) Intravenous high-dose pulsed methylprednisolone (same
dose) plus oral methotrexate 7.5 mg per week for 2 weeks, increased to 10 mg per week for
another 2 weeks then 12.5 mg per week for 5 months (total 6 months of methotrexate
treatment). Depending on patient response, the dose can be further increased by 2.5mg per
week every 4 weeks to a maximum of 20 mg per week. A strict management protocol will be
observed for each recruited patient. Patients who develop adverse side effects or need for
surgical intervention will receive appropriate treatment (i.e. treatment will deviate from
the protocol but will continue to be monitored). Patients who refuse treatment will be
observed clinically and with imaging as a natural control group until such time as
intervention is accepted.
The patients will have a baseline assessment followed by regular visits to assess treatment
response and adverse effects. Observations will include the use of an inflammatory index,
motility measurements including quantitative ductions, exophthalmometry readings, palpebral
aperture readings and indices of optic nerve function. With regards to the imaging, the
patients will be assessed with an initial quantitative CT scan and 3-Tesla MRI scan prior to
treatment. After treatment is started, patients will also undergo repeat MRI scan at 24 weeks
and 72 weeks to assess quantitative changes with treatment using the Muscle Diameter Index
(MDI) and Pixel Value Ratio (PVR) for the inferior rectus, superior rectus, the medial
rectus, lateral rectus and orbital fat (Appendix E). Serum and urine will be obtained at the
same time intervals as the MRI scan to assess levels of thyroid hormones, thyroid antibodies
and urinary glycosaminoglycans (GAGs). Free T4, free T3 and TSH will be recorded to monitor
control of hyperthyroidism. Thyroid antibodies measured will include thyroid stimulating
immunoglobulin (TSI), thyrotropin-binding inhibition antibody (TB II), thyroid peroxidase
antibodies and thyroglobulin antibody. Other tests including the full blood count, urea and
electrolytes will be run prior to each dose of steroid treatment and during follow-up to
monitor for adverse effects.
The results of the assessments will be analyzed for significant differences in treatment
response between the 2 groups. The indices of interest will include the percentage of
patients in each group who demonstrate a decrease in the inflammatory index of at least 2
points and the time taken for 50% of patients to show such a decrease. Other parameters that
reflect the visual function and motility will be compared at different points in time after
starting treatment to observe response and sustainability of response. From the serial MRI
scans, quantitative analysis of orbital tissues will be done to identify changes with
treatment. Antibody and GAG levels will be analyzed to detect any change with treatment. The
types and frequency of adverse side effects in the 2 groups will also be assessed.
80 normal subjects will be recruited for MRI scan of the orbits and brain to obtain normative
values for the MDI and PVR for the Asian population (Appendix E). This will include 20
subjects from each of 4 decades (21-30 years, 31-40 years, 41-50 years, 51-60 years).
The normative data will also be used to create a virtual orbital atlas. This aspect of the
study will be performed in collaboration with the Labs for Information Technology (A-Star).