Sirolimus as a second-line treatment for Graves’ orbitopathy

Study design

We performed an observational, single-centre, no-profit, clinical study to evaluate the effects of sirolimus as a second-line treatment on the outcome of moderate-to-severe, active GO compared to ivGCs. The investigation entailed data analysis of consecutive patients treated with either sirolimus or methylprednisolone over 18 consecutive months.

Setting

The study was carried out at the University Hospital of Pisa, a tertiary referral Centre. The study was approved by the local Ethic Committee (Comitato Etico Area Vasta Nord-Ovest, approval no. 21672_MARINO) and performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The study was registered in clinicaltrial.gov (registration no. NCT05345119).

Participants

Data analysis was conducted in consecutive patients who fulfilled the following inclusion and evaded the following exclusion criteria.

Inclusion criteria: (1) men and women aged 18–75 years; (2) moderate-to-severe, active GO, defined as the presence of at least one of the following criteria associated with a clinical activity score (CAS) ≥ 3/7 points in most affected eye: (i) exophthalmos ≥ 2 mm compared with normal for gender and race; (ii) inconstant to constant diplopia; and (iii) lid retraction ≥ 2 mm; (3) previous treatment with ivGCs, performed more than 24 weeks before the current treatment; (4) written, signed informed consent including compliance with requirements and restrictions listed in the consent form.

Exclusion criteria: (1) optic neuropathy, as defined by the 2021 EUGOGO guidelines [3]; (2) treatment with glucocorticoids or other immunosuppressive medications, and/or selenium, and/or orbital radiotherapy and/or orbital decompressive surgery in the 24 weeks preceding the current treatment; (3) mental illness preventing comprehensive informed consent.

Signed informed consent was obtained from all patients.

Outcomes

The primary endpoint of the study was the overall GO outcome at 24 weeks, based on a composite evaluation, as recommended by the 2021 EUGOGO guidelines [3, 10]. Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) improvement in 5-point CAS (spontaneous and gaze-evoked pain excluded) by at least 1 point; (2) improvement in exophthalmos by at least 2 mm; (3) improvement in lid aperture by at least 2 mm; (4) improvement in eye muscle ductions ≥ 8°; (5) improvement in visual acuity by at least 0.2/1.

Secondary objectives were: (1) improvement in QoL (comparison between the two groups at 24 weeks); (2) reduction in proptosis at 24 weeks (percentage of subjects with a reduction ≥ 2 mm without worsening in the contralateral eye); (3) reduction in CAS at 24 weeks (percentage of subjects with a reduction in CAS by at least one point); (4) improvement of eye ductions at 24 weeks (percentage of subjects with increase in eye muscle ductions ≥ 8°); (5) improvement of diplopia at 24 weeks [percentage of subjects with disappearance or improvement (change from constant to inconstant, intermittent, or absent, from inconstant to intermittent or absent, or from intermittent to absent) of diplopia]; (6) reduction in lid aperture at 24 weeks (percentage of subjects with a reduction ≥ 2 mm); (7) TSH-receptor autoantibodies (TRAbs) at 24 weeks.

Safety objectives included adverse events documented and coded according to the standardized medical dictionary for regulatory affairs (MedDRA) [11], as recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Procedures

Starting at baseline, patients in the sirolimus group received a first dose of sirolimus of 2 mg orally on the first day, given approximately at 10 am, followed by 0.5 mg per day for 12 weeks. Patients in the methylprednisolone group received intravenous methylprednisolone according to the following, previously described [3], protocol: 500 mg/weekly (6 weeks), 250 mg/weekly (6 weeks) (cumulative dose 4.5 g). Patients in the methylprednisolone group were given omeprazole 20 mg/daily across the treatment period.

Sources of data and measurements

An ophthalmological evaluation was performed at baseline and at 24 weeks, including: (1) exophthalmometry (Hertel exophthalmometer); (2) eyelid aperture; (3) assessment of diplopia (Gorman score) [3]; (4) ocular ductions; (5) corneal status; (6) fundi; (7) visual acuity (Snellen chart); and (8) CAS [12]. Patients were seen by two ophthalmologists (M.N.M, C.P) at the same time at all visits, in order to minimize inter- and intra-observer variations.

The following blood tests were performed at baseline, at 6, 12, 18, and 24 weeks: free thyroxine (FT4) and triiodothyronine (FT3), by chemiluminescence immunoassays (Vitros Immunodiagnostics, Raritan, NJ); thyroid stimulating hormone (TSH), by immunochemiluminometric assay (Immulite 2000, Siemens Healthcare, Gwynedd, UK). TRAbs were measured at baseline and at 24 weeks by enzyme-linked immunoassay (ElisaRSR™ TRAb 3rd Generation, Cardiff, UK). The following blood tests were performed at baseline and every two weeks up to 24 weeks: blood count, creatinine, AST, ALT, CPK, alkaline phosphatase, fasting blood glucose, total cholesterol, high-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides, all by enzymatic-colorimetric assays (Roche, Mannheim, Germany). Rapamycin was measured in the sirolimus group at 12 weeks by chemiluminescent microparticle immunoassay (ARCHITECT Sirolimus, Abbott, Chicago, Illinois, USA).

Quality of life (QoL) was evaluated using a specific questionnaire for GO (GO-QoL) [13]. Patients filled the questionnaire at baseline and at 24 weeks. Questionnaire consists of two subscales: (1) visual functioning (eight questions concerning limitations attributable to decreased visual acuity, diplopia, or both), and (2) appearance (eight questions referring to limitations in psychosocial functioning attributable to changes in appearance). Questions are scored as severely limited (one point), a little limited (two points), or not limited at all (three points). The total score as well as the two subscales were converted into percentages according to the following formula: (total points × 100)/(number of questions answered × 3). A higher percentage means a better QoL.

Data were collected and recorded in a database. The following database validation procedures were employed: allowed character checks, batch totals, missing records check, cardinality check, digits check, consistency check, control totals, cross-system consistency check, data type check, hash totals, limit check, logic check, presence check, range check, spelling and grammar check, and uniqueness check.

Bias

The study was not prospective neither randomized, and patients were offered treatment with sirolimus because of contraindications to methylprednisolone or if they refused methylprednisolone. In order to overcome the potential bias that could derive from lack of randomization, data analysis was conducted in patients who were not selected, but included by means of consecutive sampling. In addition, as reported below, the two study groups were similar for all features prior to treatment, which should guarantee a fair and correct comparison between the two treatment modalities.

Study size

Being an observational, retrospective analysis, a sample size could not be calculated in advance. Instead, power calculations were conducted before data analysis in order to quantify the minimum detectable difference in the primary outcome measure. Given the size of each group (15 patients per group), the number of patients we analysed was estimated to be sufficient to achieve a 80% power in order to detect a difference > 45% via a two-sided Z-Test with unpooled variance, assuming that the percentage of responders in the control group (methylprednisolone) was 30%, as reported in a recent study in which the same regimen of methylprednisolone treatment was administered to patients for the same duration and a similar outcome measure was applied [14]. Accordingly, the study was powered to detect a percentage of responders in the group of patients treated with sirolimus greater than 75%.

Statistical analyses

Continuous variables are presented as mean (SD) or median (IQR), as appropriate. Continuous variables were standardized to determine their effect on primary outcome.

Continuous variables were compared by ANOVA with Bonferroni’s correction or Mann–Whitney. Categorical data were compared by two-tailed Fisher’s exact test. Analyses were implemented using SPSS version 21.0 (IBM, New York, NY).

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