Glucocorticoids For Active Moderate-to-Severe Graves’ Ophthalmopathy

Graves’ophthalmopathy (GO) is an autoimmune disorder that usually appears in patients with Graves’disease. Orbital fibroblasts are stimulated by TSH receptor antibodies and IGF-1receptor antibodies to secrete glycosaminoglycans and hyaluronan causing clinical features commonly seen in affected individuals.The European Group on Graves’Orbitopathy (EUGOGO) grades GO broadly from mild, moderate-to-severe, to very severe conditions. GO follows a biphasic course with an active or progressive phase followed by a quiescent or stable phase. Glucocorticoid (GC) is the most common immunosupressive treatment for active moderate-to-severe disease and can be administered through oral, intravenous or local (retrobulbar or subconjunctival) routes. This meta-analysis included six randomized controlled trials comparing oral and intravenous glucocorticoids (IV GC) and confirmed that intravenous route is superior to oral route in terms of efficacy and safety thus can be regarded as first-line treatment for patients with active moderate-to-severe Graves’ophthalmopathy. Prior to treatment patients should be first screened for liver dysfunction, recent hepatic viral infections, hypertension, et al, and then monitored for side effects.Discussion regarding IV GC therapy for GO has shifted from whether this therapy should be used, to which treatment protocol optimizes efficacy and minimizes morbidity. Two protocols that have been widely used for the past decade are as follows:(1) weekly protocol:0.5g methylprednisolone weekly for six weeks followed by0.25g weekly for six weeks;(2) daily protocol:0.5g daily for three consecutive days per week for two weeks, followed by0.25g daily for three consecutive days per week for another two weeks and by tapering oral prednisone. Both protocols are effective and well tolerated. Future randomized trials are needed to determine the optimal IV GC protocol for active moderate-to-severe GO and what we can do when steroid treatments fail. Part One:Graves’Ophthalmopathy-from Concept to Clinical PracticeThe main mechanism of Graves’ophthalmopathy consists of an increased secretion of glycosaminoglycans and hyaluronan by orbital fibroblasts leading to proptosis and extra-ocular muscle swelling. TSH receptor antibody and IGF-1receptor antibody are two most important auto-antigens. The diagnosis of GO relys predominantly on clinical features. Grading systems for GO include NO SPECS, EUGOGO’s severity scales and the Clinical Activity Score (CAS) although they are not without defects. Our understanding of Graves’ophthalmopathy points to several potential therapeutic targets. Glucocorticoids represent first-line therapy for active moderate-to-severe GO and sight-threatening conditions. Rituximab and small molecular antagonist of TSH receptor might have a promising future but randomized controlled trials are required to confirm their efficacy. Part Two:Intravenous and Oral Glucocorticoids for Active Moderate-to-Severe Graves’Ophthalmopathy:A Meta-Analysis of Randomized Controlled TrialsBackgroundGraves’ophthalmopathy is an autoimmune disorder representing the commonest and most important extrathyroidal manifestation of Graves’ disease. It has a significant impact on everyday life and represents a major clinical and therapeutic challenge. GO is often mild and self-limiting, with only3-5%of cases posing a threat to eyesight. A questionnaire survey has shown that suboptimal management of patients with GO appears to be widespread in Europe. Thus forming an appropriate workup for GO is of vital importance for improving the clinical outcome and quality of life.Glucocorticoids have been used as the most common immunosuppressants in the treatment of active and severe GO for more than half a century. The aim of the treatment is to decrease inflammation and congestion of the orbital tissue, thereby trying to prevent clinical progression. Numerous studies have demonstrated that IV GC is superior to the oral route which is less efficacious and associated with more frequent adverse events. But results vary in terms of response rates and the proportion of side effects. This study is designed to compare the intravenous route and the oral route.ObjectiveTo assess the efficacy and safety of oral and intravenous glucocorticoids in the treatment of active moderate-to-severe Graves’ ophthalmopathy.Methods PubMed and the Cochrane database were searched to identify all studies regarding intravenous glucocorticoids for Graves’ophthalmopathy before January of2014. Inclusion criteria were as following:(1) randomized controlled trials were designed;(2)active and moderate-to-severe GO patients were studied;(3)intravenous and oral routes were compared. Response rates and adverse events were determined as primary outcomes. Relative risk with95%confidence interval was used for comparison between two ways of administering steroids. Fixed or random effects model was used according to the presence of heterogeneity.ResultsA total of six randomized controlled trials involving321patients were included in this meta-analysis. The pooled RR of response rates is1.49(95%CI1.28to1.74, P<0.00001) suggesting increased response rates associated with intravenous route compared with the oral route. The pooled RR of adverse events is0.57(95%CI0.45to0.73, P<0.00001) suggesting the intravenous route is much safer.ConclusionsThis meta-analysis confirmed that IV GC is advantageous over oral administration in terms of efficacy and safety thus should be regarded as the first choice in the treatment of active moderate-to-severe G0. Part Three:Intravenous Glucocorticoids for Active Moderate-to-Severe Graves’OphthalmopathyIV GC is currently regarded as the first-line treatment for active moderate-to-severe Graves’ophthalmopathy. Randomized controlled trials and meta-analyses have confirmed that intravenous administration is more effective and better tolerated than oral administration but the optimal IV GC protocol remains controversial. From the late1980th IV GC protocols have evolved from1g methylprednisolone daily for three consecutive days, to0.5g daily for three consecutive days with varying durations as more major adverse events were reported. EUGOGO suggested a weekly protocol of0.5g methylprednisolone weekly for six weeks followed by0.25g weekly for six weeks, which along with the0.5g daily protocol, have been widely adopted for the past decade. Prior to treatment liver dysfunction and recent hepatic viral infection should be excluded and a history of hypertension, diabetes mellitus and peptic ulcers should be acquired. Patients should be monitored during the course. This review sumarizes all major studies on IV GC protocol and draws the conclusion that both daily and weekly protocol are efficacious and safe with a possible superiority of the latter confirmed by one multi-centered, randomized trial. More studies are needed to determine the best IV GC protocol and the treatment strategies of active moderate-to-severe GO when GC fails.