Factors Predicting Long-term Outcome and the Need for Surgery in Graves Orbitopathy: Extended Follow-up From the CIRTED Trial.

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. METHODS: Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. RESULTS: Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves' Orbitopathy score, or Ophthalmopathy Index.Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. CONCLUSION: In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes.

The Effect of Ophthalmic Surgery for Graves' Orbitopathy on Quality of Life: A Systematic Review and Meta-Analysis.

Background: Graves' orbitopathy (GO) has a profound negative impact on quality of life. Surgery is undertaken to preserve vision, correct diplopia, and improve aesthetics. We sought to quantify the effect of different surgical approaches on quality of life. Methods: Electronic databases Ovid-MEDLINE and EMBASE were used from inception until March 22, 2021, to identify studies assessing quality of life pre- and postsurgical intervention for GO. Two reviewers independently extracted data and performed quality assessments. Random-effects and Bayesian models for meta-analyses were utilized. Results: Ten articles comprising 632 patients with a mean age of 48.4 years (range 16-85 years) were included. All used the Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire. For GO-QOL appearance, the pooled standardized mean improvement for patients after surgery was +0.72 (95% confidence interval [CI 0.50-0.94]), I2 = 69% [CI 52-80%]. For GO-QOL visual functioning, the pooled standardized mean difference (SMD) for patients after surgery was +0.41 [CI 0.25-0.58], I2 = 60% [CI 36-74%]. For visual appearance, orbital decompression yielded the greatest improvement (SMD +0.84 [CI 0.54-1.13]) followed by eyelid surgery (SMD +0.38 [CI 0.05-0.70]), while strabismus correction had no significant effect (SMD +0.94 [CI -0.10 to 1.99]). Conversely strabismus correction was associated with the greatest improvement (SMD +1.25 [CI 0.29-2.21]) in visual functioning, outperforming orbital decompression (SMD +0.29 [CI 0.15-0.43]) and eyelid surgery (SMD +0.12 [CI -0.18 to 0.41]). A mean improvement in GO-QOL of greater than 10 points after orbital decompression surgery was achieved in 12/14 (86%) patient groups for appearance and 5/14 (36%) patient groups for visual functioning. A mean improvement of greater than 6 points was achieved in 5 of 6 (83%) patient groups for strabismus surgery for both appearance and visual functioning. A mean improvement of greater than 6 points after eyelid surgery was achieved in 2/3 (67%) patient groups and 0/3 patient groups for visual appearance and functioning, respectively. Conclusion: Ophthalmic surgery results in substantial improvements in quality of life in patients with GO, with greater perceived effects on appearance than visual function. Orbital decompression has particular impact on visual appearance; strabismus surgery may benefit both visual appearance and function equally, whereas eyelid surgery benefits appearance alone.

Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial.

BACKGROUND: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. METHODS: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for ≥80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to-treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. FINDINGS: Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98-6·66, p=0·054) for azathioprine and 0·89 (0·36-2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66-28·1, p=0·008) for azathioprine and 1·32 (0·30-4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. INTERPRETATION: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. FUNDING: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Early partial division of a hughes tarso-conjunctival flap with secondary intention healing of the anterior.

A 61-year-old man had a highly myopic amblyopic right eye since birth but retained good unaided vision of 6/5 in his left eye. He presented with an enlarging lesion of his left lower lid. The clinical appearance was consistent with a large basal cell carcinoma. Excision biopsy resulted in a defect measuring 18mm horizontally and 8mm vertically. The left eye was padded for 2 days and urgent paraffin section histology confirmed complete excision of a basal cell carcinoma. The lower lid defect was repaired with a Hughes tarsoconjunctival flap and the eye was padded for a further 5 days to aid the healing process. At this time, the flap was partially divided at the medial end to allow earlier visual rehabilitation, whilst the undivided lateral part of the flap continued to provide lift. The anterior lamella was left to heal by secondary intention and division of the remaining lateral portion of the flap was finally completely divided 4 weeks later by which time the anterior lamella was well healed. Both functional and cosmetic results were very satisfactory.

Orbital radiotherapy for adult thyroid eye disease.

BACKGROUND: Thyroid eye disease is an autoimmune inflammatory condition of the orbital and periorbital tissues. Orbital radiotherapy is an anti-inflammatory treatment used in the treatment of active thyroid eye disease. It is administered as an outpatient procedure in 10 to 12 fractionated doses. OBJECTIVES: To assess the effectiveness and adverse events of orbital radiotherapy in thyroid eye disease. The effectiveness was dependent on the level of 'success' of the intervention predefined in each randomised controlled trial (RCT). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 2), MEDLINE (January 1950 to March 2012), EMBASE (January 1980 to March 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to March 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not restrict the electronic searches for trials by date or language. We last searched the electronic databases on 12 March 2012. We screened reference lists of reports of included studies, other reviews and book chapters to find additional trials. We contacted trial investigators and experts in the field to identify additionally published studies. SELECTION CRITERIA: We included RCTs of orbital radiotherapy versus sham radiotherapy or other interventions enrolling adults, with a minimum of three months' follow-up and an endpoint of two years or less post treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Trial authors were contacted for missing data. The risk ratio was used for our primary outcome. For our secondary outcomes, the odds ratio and mean difference were reported where possible. MAIN RESULTS: We obtained full-text copies of nine potential studies and included five trials with a total of 244 participants in this review. Orbital radiotherapy was compared to sham radiotherapy in two studies and to glucocorticoids in three studies, as a monotherapy or combination therapy. There was heterogeneity (as defined in our protocol) of trial outcome measures. Our primary outcome of a composite score was used in the two trials comparing radiotherapy versus sham radiotherapy and showed a risk ratio of success of 1.92 (95% confidence interval (CI) 1.27 to 2.91) in favour of orbital radiotherapy. The primary outcome was not used in the other three trials. AUTHORS' CONCLUSIONS: This review found that orbital radiotherapy is more effective than sham radiotherapy for the treatment of mild-to-moderate thyroid eye disease. In a single trial no difference between radiotherapy and steroid monotherapy was found. A meta-analysis of our secondary outcome of disease severity was not possible but results from individual trials suggest a better outcome with combination treatment with steroids versus steroids alone. No significant changes in quality-of-life scores following treatment with radiotherapy versus alternative treatments were found. Short-term adverse events related to radiotherapy that were reported were local and mild but long-term data were lacking and development of retinal changes following radiotherapy was not reported on.

Smoking and strabismus surgery in patients with thyroid eye disease.

OBJECTIVE: To investigate the relationship between smoking status at presentation and the use of strabismus surgery in the management of patients with thyroid eye disease. DESIGN: Retrospective review of a noncomparative series of patients with thyroid eye disease. PARTICIPANTS: All patients with thyroid eye disease under the care of a single consultant at Moorfields Eye Hospital between 1997 and 2002 (inclusive). METHODS: Retrospective review of clinical case notes. MAIN OUTCOME MEASURES: Survival analysis of patients in cohort and the frequency of strabismus surgery in relation to smoking status at ophthalmic presentation. A subanalysis of patients who underwent orbital decompression and those that did not was undertaken. RESULTS: Of 501 patients seen during the study period, 425 (85%) of 501 sets of notes were available for review, and initial smoking status was recorded for 89% (378/425) of patients, of whom approximately one half (196/378; 52%) were active smokers. Of the smokers, 51 (26%) of 196 underwent strabismus surgery, compared with only 19 (14%) of 138 nonsmokers at presentation. When adjusted for age, the hazards ratio of having strabismus surgery during management for smokers at presentation versus nonactive smokers was 2.19. In the group who did not undergo orbital decompression, this hazard ratio increased to 4.86. CONCLUSIONS: Within this thyroid eye disease cohort, the proportion of smokers at presentation was much larger than that of the general population. There was an increased use of strabismus surgery in active smokers at presentation than in nonactive smokers. This finding was independent of the orbital decompression surgery. The results are consistent with those of previous reports of more severe thyroid eye disease in smokers and raise the possibility that smoking cessation early in the disease may reduce the severity of the changes and the number of rehabilitative strabismus operations needed. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Protocol for the combined immunosuppression & radiotherapy in thyroid eye disease (CIRTED) trial: a multi-centre, double-masked, factorial randomised controlled trial.

BACKGROUND: Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes. Glucocorticoids are known to be effective initially but have significant side-effects with long-term use and recrudescence can occur on cessation. Current evidence is conflicting on the efficacy of radiotherapy and non-steroid systemic immunosuppression, and the majority of previous studies have been retrospective, uncontrolled, small or poorly designed.The Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease (CIRTED) trial was designed to investigate the efficacy of radiotherapy and azathioprine in combination with a standard course of oral prednisolone in patients with active thyroid eye disease. METHODS/DESIGN: Patients with active thyroid eye disease will be randomised to receive (i) azathioprine or oral placebo and (ii) radiotherapy or sham-radiotherapy in this multi-centre, factorial randomised control trial. The primary outcome is improvement in disease severity (assessed using a composite binary measure) at 12 months and secondary end-points include quality of life scores and health economic measures. DISCUSSION: The CIRTED trial is the first study to evaluate the role of radiotherapy and azathioprine as part of a long-term, combination immunosuppressive treatment regime for Thyroid Eye Disease. It will provide evidence for the role of radiotherapy and prolonged immunosuppression in the management of this condition, as well as pilot data on their use in combination. We have paid particular attention in the trial design to establishing (a) robust placebo controls and masking protocols which are effective and safe for both radiotherapy and the systemic administration of an antiproliferative drug; (b) constructing effective inclusion and exclusion criteria to select for active disease; and (c) selecting pragmatic outcome measures. TRIAL REGISTRATION: Current controlled trials ISRCTN22471573.