Hypercholesterolemia, Thyroid Associated Ophthalmopathy
Conditions
Brief summary
Graves' orbitopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease (GD), being observed in \ 25% of patients. Besides genetic and demographical variables, risk factors associated with the development of GO in GD patients are known to be inadequate control of hyperthyroidism, radioiodine treatment, and smoking. In a large retrospective study conducted in more than 8,000 individuals with GD it was observed that treatment with 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, better known as statins, is associated with a \ 40% reduced risk of developing GO in GD patients. The findings were interpreted as the consequence of the anti-inflammatory action of statins, being GO notoriously an autoimmune, inflammatory conditions. Statins are widely used for the treatment of hypercholesterolemia, for which they are quite effective. The possibility that their protective effect in terms of GO development in GD patients, as observed by Stein et al., was simply due to their hypolipemic actions was not considered. To evaluate the possibility that the findings reflected lowering of cholesterol rather than a direct anti-inflammatory effect of statins a prospective, observational study to assess the association between GO and high cholesterol levels and/or the relationship between the degree and/or activity of GO and hypercholesterolemia is ongoing. Preliminary findings suggest that GO is more severe and active in patients with high cholesterol levels. On the basis of these observations, the present randomized clinical trial was designed to be performed in hypercholesterolemic patients with GD and moderate-to-severe and active GO, aimed at investigating if lowering of cholesterol levels with statins is associated with a better outcome of GO.
Interventions
DRUGAtorvastatin
Atorvastatin 20 mg daily
DRUGMethylprednisolone
500 mg of methylprednisolone weekly for 6 weeks, followed by 250 mg weekly for another 6 weeks, for a total dose of 4.5 mg.
Sponsors
University of Pisa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Ophthalmologist blinded to treatment
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Informed consent 2. A diagnosis of Graves' disease 3. A moderately severe GO 4. Active GO 5. No corticosteroids or immunosuppressive treatment for GO in the last 3 months. 6. No previous surgical treatment for GO 7. No contraindication to GC 8. Male and female patients of age: 18-75 years 9. LDL-cholesterol levels of 115-189 mg/dl 10. No more than one cardiovascular risk factor (diabetes, high blood pressure, smoking, familial history of acute cardiovascular events, obesity) 11. Effective method of contraception 12. No mental illness that prevent patients from comprehensive, written informed consent 13. Compliant patient, regular follow-up possible
Exclusion criteria
1. lack of informed consent 2. Absence of Graves' hyperthyroidism (present or past) 3. Inactive GO 4. Optic neuropathy 5. Corticosteroids or immunosuppressive treatment for GO in the last 3 months. 6. Previous surgical treatment for GO 7. Contraindications to GC 8. Pregnancy, breast-feeding women 9. Acute or chronic liver disease 10. Hypersensitivity to atorvastatin or other statins, or hypersensitivity or intolerance to the medication excipients such as lactose. 11. Medications interfering/interacting with statins (CYP3A4 inhibitors or inductors) 12. Relevant Malignancy 13. Corticosteroids or other immunosuppressive agents within last 3 months 14. Recent (≤1 year) history of alcoholism or drug abuse 15. Clinical ASCVD (AthroSclerotic CardioVascular Disease) 16. LDL-cholesterol levels ≥190 mg/dl or presence of more than one associated cardiovascular risk factor (diabetes, high blood pressure, smoking, familial history of acute cardiovascular events, obesity) 17. Severe familial hyperlipemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall GO outcome determined using a composite evaluation | 6 months | Overall GO outcome determined using a composite evaluation. A composite evaluation of GO was described previously. Possible outcomes are: improvement, worsening, no change, resulting in 3 categorical values Improvement: amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes: Deterioration: worsening in two parameters in at least one eye: All other cases are no change Parameters are: Eyelid swelling (improvement/worsening according to EUGOGO Atlas evaluation) Lid aperture in mm (significant variation: 2 or more mm) Clinical activity score (CAS) (7 items: spontaneous pain, evoked pain, eyelid edema, eyelid redness, conjunctiva redness, caruncle edema, chemosis; significant change: at least 2 points) Exophthalmos in mm (significant variation 2 or more mm) Eye muscle involvement - diplopia score (Gorman score) (significant variation: disappearance or change in the degree, or improvement of ≥12 degrees in motility) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall GO outcome determined using a composite evaluation | 3 months | Overall GO outcome determined using a composite evaluation. A composite evaluation of GO was described previously. Possible outcomes are: improvement, worsening, no change, resulting in 3 categorical values Improvement: amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes: Deterioration: worsening in two parameters in at least one eye: All other cases are no change Parameters are: Eyelid swelling (improvement/worsening according to EUGOGO Atlas evaluation) Lid aperture in mm (significant variation: 2 or more mm) Clinical activity score (CAS) (7 items: spontaneous pain, evoked pain, eyelid edema, eyelid redness, conjunctiva redness, caruncle edema, chemosis; significant change: at least 2 points) Exophthalmos in mm (significant variation 2 or more mm) Eye muscle involvement - diplopia score (Gorman score) (significant variation: disappearance or change in the degree, or improvement of ≥12 degrees in motility) |
| Comparison of a disease specific quality of life questionnaire (GO-QoL) | 6 months | A GO-specific quality of life questionnaire (GO-QoL) comprises 16 items, 8 concerning appearance and 8 concerning function. The combination of the various parameters gives a final numeric value which will be compared between the two groups |
| GO relapse | 6 months | Worsening in comparison with the 3-month evaluation |
| Requirement for additional treatments | 3 months | Additional intravenous glucocorticoids, radiotherapy, orbital decompression, immunosuppressive treatments of any kind |
Countries
Italy
Outcome results
None listed