Endocrine Abstracts

Background: Sirolimus is an immunosuppressive drug with anti-fibrotic and anti-proliferative activities. In vitro, sirolimus inhibits differentiation of orbital fibroblasts from patients with Graves’ orbitopathy (GO), suggesting a possible use in clinical practice.

Methods: We performed a retrospective investigation aimed at evaluating the effects of sirolimus as a second-line treatment for moderate-to-severe, active GO, compared with methylprednisolone. The investigation entailed data analysis of unselected, consecutive patients with moderate-to-severe, active GO, treated off-label with sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)], as a second-line treatment, over a period of 18 consecutive months. The primary objective was the overall GO outcome at 24 weeks based on a composite evaluation. Secondary objectives at 24 weeks were: 1) improvement in quality of life, evaluated using a specific questionnaire (GO-QoL); 2) reduction of proptosis; 3) reduction of the clinical activity score (CAS); 4) improvement of eye ductions; and 5) reduction of eyelid aperture.

Results: Data from 30 patients (15 per group) were analyzed. Baseline demographic and clinical features did not differ between the two groups. The proportion of overall GO responders (primary outcome) was significantly greater in the sirolimus group compared with the methylprednisolone group (80% vs 26.6%; OR: 11; 95% CI from 1.9 to 60.5; P=0.0059). The total GO-QoL score at 24 weeks was greater in the sirolimus group (mean difference 5.5 points; 95% CI from 1.4 to 9.6, P=0.010). The proportion of proptosis responders was greater in the sirolimus group (80% vs 13.3% in the methylprednisolone group; OR: 26; 95% CI from 3.6 to 183.4; P=0.0011), as was the proportion of CAS responders (86.6 vs 33.3%, OR: 13; 95% CI from 2 to 81.4; P=0.0062). In contrast, eyelid width and eye ductions responders did not differ between the two groups. No serious adverse events were observed, with no differences between the two groups.

Conclusions: Given the limitations of a retrospective investigation, sirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observation and to investigate whether sirolimus can be employed as a first line treatment. To our knowledge, apart from two previous case reports, this is the first report on sirolimus for GO in a patient series.