TOPIC: Graves' orbitopathy
Title: Methylprednisolone pulse therapy for patients with moderately severe Graves' orbitopathy: a prospective, randomized, placebo-controlled study.
Authors: Van Geest RJ, Sasim IV, Koppenschaar HP, Kalmann R, Stravers SN, Bijlsma WR, & Mourits MP .
Reference: European Journal of Endocrinology 158: 229-237, 2008
Glucocorticoids, administered through different routes, are a mainstay in the management of Graves' orbitopathy (GO), but the proof of their effectiveness resides with the comparison with other treatment, while no comparison with placebo has ever been carried out.
To compare the effectiveness of intravenous (iv) glucocorticoids with that of placebo in a prospective, randomized study of patients with moderately severe GO.
Material & Methods
Patients with moderately severe and active GO were randomly assigned to either iv pulse glucocorticoid treatment (the cumulative dose was 6 g of methylprednisolone over a 3-month period) or placebo. Of a total of 46 eligible patients, 30 refused to participate. Accordingly 6 patients were allocated into the glucocorticoid group and 9 were assigned to placebo.
A clinical beneficial response, assessed on the basis of predefined criteria, was observed in 5 of 6 (83%) glucocorticoid-treated patients and in only 1 of 9 (11%) placebo-treated patients (P = 0.005). Glucocorticoid treatment was well tolerated without major side effects.
This placebo-controlled study confirms that glucocorticoids represent an effective therapy for moderately severe and active GO.
Glucocorticoids have been used for decades for the management of moderate-to-severe (or sight-threatening) and active forms of GO because of their anti-inflammatory and immunosuppressive actions. In general, about 60-65% favourable responses have been reported in various studies over the years. The assumption that these beneficial effects are really attributable to glucocorticoid action was based on the comparison with other therapeutic agents, such as orbital radiotherapy, cyclosporine, somatostatin analogs, which all provided less satisfactory results. Thus, although the bulk of the evidence supports the idea of a true effectiveness of glucocorticoids on active GO, characterized mainly by inflammatory changes of different degrees, no study had insofar tested the hypothesis that the observed amelioration might be accounted for, partly or completely, by the natural eye disease history. The latter is incompletely understood but, according to the limited evidence available in the literature, it is conceivable that GO, once it has developed, may over a period of one-two years remain unchanged, or progress to more severe forms, or even spontaneously improve or regress, although almost invariably incompletely.
The study by Van Geest et al. is the first in which glucocorticoids, given iv, were compared with placebo. The results clearly showed that drug treatment was much more effective than placebo, in terms of the overall GO amelioration (83% vs 11%), but also of improvement of individual features (soft tissue changes, diplopia, clinical activity score), with the exception of proptosis and lid width. In view of concerns regarding toxicity (particularly liver toxicity) of high-dose iv glucocorticoids, it is worth noting that no major untoward effect was observed, confirming that a cumulative dose of methylprednisolone of less than 8 g per course is probably safe.
The main limitation of present study was the small number of patients enrolled. Of a total of 46 eligible patients, only 16 were recruited because two thirds refused (for several reasons). For this reason, the results should be interpreted with caution. Nevertheless, differences between the glucocorticoid and placebo groups were really striking. Accordingly, this small study provides a fairly strong evidence that the beneficial effects of glucocorticoids, reported over the years, do not reflect a spontaneous amelioration of eye involvement (i.e. the natural history) but are actually drug-induced.
Several issues on the use of iv glucocorticoids for moderate-to-severe GO remain to be clarified, once it has been confirmed that they are truly effective and that the iv route is better than the oral route in terms of effectiveness and tolerability. What is the optimal cumulative dose? What should the duration of treatment be? Is the combination with orbital radiotherapy going to provide better results that either treatment alone, as it has been demonstrated using oral glucocorticoids? Are novel treatments on the horizon, more effective than intravenous glucocorticoids?
Presently, we have no answers to these questions that should be addressed by future randomized clinical trials.
Full paper obtainable at http://www.eje-online.org
Summary and commentary prepared by Luigi Bartalena (Related to Chapter 12 of TDM)