LAUSR

Graves’ orbitopathy (GO) is the main non-thyroidal expression of Graves’ disease [1]. Management of moderate-tosevere and active forms of the disease remains a major and not completely solved therapeutic challenge and dilemma [2]. Glucocorticoids are, for the time being, the first-line treatment, usually given intravenously in 12 weekly infusions, with a cumulative dose of 2.5–7.5 g of methylprednisolone, more commonly 4.5 g [2]. Intravenous glucocorticoids are effective, particularly in inactivating the disease, but some features of GO, namely exophthalmos and longstanding extraocular muscle restriction, are not very responsive [2]. Treatment is more effective if duration of GO is < 1 year [1]. Relapses after treatment withdrawal are not infrequent [2]. In addition, large doses of glucocorticoids are needed, and this may cause severe adverse events, including liver toxicity, hypertension, diabetes, psychosis [2]. Therefore, the addition of a second drug aimed at reducing the dose of glucocorticoids might be reasonable. Indeed, many years ago, the combination of oral glucocorticoids and cyclosporine resulted in a favorable outcome in patients unresponsive to either treatment alone and permitted the use of a lower dose of oral steroids [3]. Likewise, combination of orbital radiotherapy with oral glucocorticoids was more effective than either treatment alone, but the dose of steroids was not reduced in the combination therapy [4]. Furthermore, the combination of intravenous glucocorticoids and mycophenolate recently proved to be more effective than intravenous glucocorticoids alone, but, again, the dose of steroids was the same in the two groups [5]. Finally, the addition of azathioprine to oral prednisolone seemed to be associated with an improved clinical outcome [6]. A recent single-center study from UK retrospectively evaluated 24 patients with moderate-to-severe and active GO, who were treated concomitantly with intravenous glucocorticoids and a steroid-sparing agent, in most cases (23 of 24 patients), methotrexate (20–25 mg per week orally or subcutaneously, with folic acid supplementation, given for an average of 13 months); in the case of an inadequate response, a second and a third steroid-sparing agent (most commonly cyclosporine, but also, in a few cases, azathioprine or rituximab) were added [7]. The results of this study showed that the mean cumulative dose of intravenous methylprednisolone (2.72 g) required to inactivate GO was lower than the 4.5-g cumulative dose recommended by recent guidelines (4.5 g), and in nine patients (38%) was ≤ 1.5 g [7]. Most patients had a favorable treatment outcome in terms of regression of inflammatory changes, but three patients had to withdraw methotrexate because of impaired liver function tests, chronic cough, and recurrent cystitis [7]. Although interesting in principle, this study has several limitations, essentially bound to its retrospective nature. The series is small, duration of GO was rather long, detailed information on baseline as well as on treatment-driven changes in exophthalmos, diplopia and overall severity is lacking, and, most importantly, a control group of patients treated with intravenous methylprednisolone alone is missing. Because the 24 patients included in the study were extracted from a larger series of 104 patients, probably an adequately matched group of patients given intravenous methylprednisolone alone might have been added for comparison. Therefore, this study suggests, but does not prove that this combination drug regimen is steroid sparing. This * L. Bartalena [email protected]