Antonella Boschi

Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO

Summary of consensus a. All patients with GO should (Fig. 1):Be referred to specialist centers;Be encouraged to quit smoking;Receive prompt treatment in order to restore andmaintain euthyroidism.b. Patients with sight-threatening GO should be treatedwith i.v. GCs as the first-line treatment; if the responseis poor after 1–2 weeks, they should be submitted tourgent surgical decompression.c. The treatment of choice for moderate-to-severe GO isi.v. GCs (with or without OR) if the orbitopathy isactive;surgery(orbitaldecompression,squintsurgery,and/or eyelid surgery in this order) should beconsidered if the orbitopathy is inactive.d. In patients with mild GO, local measures and anexpectant strategy are sufficient in most cases, buttreatment may be justified if QoL is affectedsignificantly. In memoriam This document is dedicated to the memory of MarkPrummel (1956–2005), one of the founders ofEUGOGO, who greatly contributed to expanding ourunderstanding of clinical and therapeutic aspects of GO.

Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy.

Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy

BACKGROUNDnOptimal doses of i.v. glucocorticoids for Graves orbitopathy (GO) are undefined.nnnMETHODSnWe carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of three doses of i.v. methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit.nnnRESULTSnOverall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98-group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit.nnnCONCLUSIONSnThe 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO.

PREGO (presentation of Graves’ orbitopathy) study: changes in referral patterns to European Group On Graves’ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012

Background/aims The epidemiology of Graves’ orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. Methods Prospective observational study of European Group On Graves’ Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. Results The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16u2005months) and from first symptoms of GO (9 vs 16u2005months) or from diagnosis of GO (6 vs 12u2005months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). Conclusions These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PurposeIntravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves’ orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive.MethodsOur database (Bartalena et al. J Clin Endocrinol Metab 97:4454–4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47xa0g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as “Improved”, “Unchanged”, “Deteriorated”, compared to baseline.ResultsDeteriorated patients at 6 weeks for CI (nu2009=u20098) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (nu2009=u200951) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (nu2009=u2009100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes.ConclusionsPatients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Bilateral transient visual obscurations with headaches during alpha-II interferon therapy: a case report.

A 40 year-old woman receiving alpha interferon therapy for chronic active hepatitis C presented transient bilateral visual obscurations with associated visual field defects and headaches, with elevated cryoglobulin levels. These manifestations mimicked the clinical picture of migraine and were associated with worsening of previous moderate Raynauds syndrome and diffuse paraventricular lesions of the white matter seen in cerebral MRI. Bilateral posterior cerebral transient ischemic episodes rather than an anterior visual pathway lesion were thought to be responsible for the clinical symptoms though the exact role of interferon in these vasospastic-like disorders remains speculative. Their possible relationship with increased cryoglobulinemia is uncertain. We suggest that Raynauds phenomenon may have a predisposing role for these manifestations.

Long-term multidisciplinary follow-up of unilateral thyroid-associated orbitopathy.

BACKGROUNDnThyroid-Associated Orbitopathy (TAO) is an autoimmune disease characterized by orbital inflammation involving both adipose tissue and extra-ocular muscles (EOM). Whereas bilateral and possibly asymmetric orbital involvement is commonly found at radiological work-up, mono-orbital involvement is poorly documented, and ascribed to an initial and/or transient stage of subsequent bilateral TAO.nnnMETHODSnFrom a cohort of two hundred TAO patients, we selected retrospectively fourteen patients with initial clinical unilateral TAO. Five of them were excluded because of clinical bilateralization.nnnRESULTSnThe sex ratio was 0.8 (4M, 5F), and mean age 44.6 years (range: 18-63). All patients were euthyroid when the initial magnetic resonance imaging (MRI) was performed. One patient was treated with Levothyroxine, because of subclinical hypothyroidism. Eight patients (six smokers) suffered from Graves disease, of 1-4 years duration, for which they were treated with antithyroid drugs. A thyroidectomy was performed in two patients. None of the patients ever received radioiodine. Six patients remained euthyroid after stopping of the antithyroid regimen, and two became hypothyroid. Seven patients had active, and two severe TAO. Four of nine patients exhibited bilateralization of TAO on initial MRI. Clinical status ultimately improved or normalized in all. In two patients, MRI performed after 9 years demonstrated partial shrinkage of previously enlarged EOMs, together with fatty involution of involved muscles.nnnCONCLUSIONSnUnilateral TAO is not different and just as severe as bilateral TAO. At initial work-up MRI shows signs of bi-laterality in 45% (4/9), with mild involvement of 1 or 2 extra-ocular muscles. The radiological status of affected muscles does not normalize, even in the very long term.

Susac syndrome in four male patients.

Purpose: To report the clinical and imaging features in four male patients presenting with Susac syndrome, a microangiopathy affecting the brain, the retina, and the cochlea. Methods: Retrospective review of clinical data, fluorescein angiograms, and magnetic resonance imaging findings in these four cases. Results: All four patients were young men (range, 20–35 years). The axiomatic triad of ocular, cochlear, and neurologic involvement was present in three patients. Neurologic symptoms were absent in the fourth one. Fluorescein angiography showed arteriolar wall hyperfluorescence in all four patients. Magnetic resonance images showed in three patients multifocal hyperintense lesions in the white matter and the corpus callosum with typical involvement of the central fibers. Therapeutic modalities and clinical course are described. Three patients had a follow-up of 3, 5, and 13 years with complete remission of the disease within 1 year in all three cases. One patient had severe neuropsychological sequelae. Conclusion: Susac syndrome seems to be less unusual in men than previously reported. Though presenting as a self-limited monophasic course disease in most cases, it may result in severe neuropsychological sequelae. Early diagnosis of the syndrome is enabled by the combination of the ophthalmologic, audiometric, and brain magnetic resonance features.

Malignant bilateral exophthalmos and secondary glaucoma in iatrogenic Cushing's syndrome.

The authors describe a case of iatrogenic Cushings syndrome in which an emergency orbital decompression was performed. This procedure was necessary because major ocular hypertension and severe bilateral exophthalmos had caused a decrease in visual function and recurrent painful episodes of eyeball luxation.

Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial

BACKGROUNDnEuropean guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves orbitopathy.nnnMETHODSnMINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93.nnnFINDINGSn164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92-3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09-4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17-3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12-3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23-4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1-2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48).nnnINTERPRETATIONnAlthough no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves orbitopathy.nnnFUNDINGnNovartis, Germany.