regimen should be employed in patients with severe GO if conservative therapy, rather than orbital decompression, is selected (1).

Immunosuppressive Drugs

Cyclosporine is the immunosuppressive drug that has been more thoroughly evaluated in the management of GO (12). Several studies have reported favorable results but only two were randomized and controlled. Thus, the favorable effects of cyclosporine reported in most uncontrolled studies must be interpreted with caution. Prummel et al. (13) indicated a lower efficacy of cyclosporine compared to prednisone as a sin- gle-agent treatment, but both Prummel et al. (13) and Kahaly et al.(5) suggested that a combination of cyclosporine and prednisone may be more effective than either treatment alone. Thus, the use of cyclosporine might be maintained, in association with glucocorticoids, in patients who are resistant to glucocorticoids alone and in whom the persistent activity of the disease warrants a continuing medical intervention. Side effects of cyclosporine cannot be neglected; some of them can be severe, calling for caution in the use of this drug. Doses lower than 7.5 mg=kg=day probably should be employed. Another immunosuppressive agent that is currently being evaluated in patients with GO is methotrexate. However, it has not systematically been evaluated in the management GO.

Plasmapheresis

The rationale for the use of plasmapheresis in the treatment of GO is based on the assumption that this procedure might remove either immunoglobulins or immune complexes possibly involved in the pathogenesis of the disease. The use of plasmapheresis provided conflicting results, since both favorable effects and treatment failures were reported (1). No study on the effects of plasmapheresis was randomized and controlled, and the interpretation of results is made even more difficult by the frequent concomitant (or subsequent) treatment with glucocorticoids or immunosuppressive drugs

(azathioprine or cyclophosphamide). In addition, recurrences of eye disease that required further courses of plasmapheresis were relatively frequent. Thus, plasmapheresis should be regarded as a ‘‘desperate’’ treatment for severe GO, when other therapies have failed (4).

Somatostatin Analogues

Expression of different subtypes of somatostatin receptors was demonstrated in the various cellular components of orbital tissue (14). Somatostatin receptors can be visualized in vivo in orbital tissue of Graves’ patients by octreoscan. Patients with active GO have a higher orbital uptake of the tracer than those with inactive eye disease. These findings led to the idea of using somatostatin in the management of GO (15).

A few uncontrolled studies of patients treated with 0.1 mg subcutaneous octreotide three times daily for 3 months have shown an improvement in soft tissue inflammatory changes and extraocular muscle impairment. These beneficial effects were achieved in patients who had positive octreoscans prior to treatment.

A major limitation of octreotide is its short half-life, which requires multiple daily injections. Krassas (15) has reported that lanreotide, a long-acting analogue (40 mg every other week for 3 months) was also effective in most patients, with no differences between the subgroup treated with octreotide and the subgroup treated with lanreotide.

In summary, the available data indicate favorable effects of somatostatin analogues in approximately 80% of patients. However, the number of patients thus far treated is too limited and it is therefore difficult to draw definite and sound conclusions on the real effectiveness of somatostatin analogues. Properly controlled studies enrolling a larger number of patients are warranted.

Intravenous Immunoglobulins

High-dose intravenous immunoglobulins (IVIG) have been used effectively in a number of autoimmune diseases. In a

randomized study, the effects of IVIG either alone or in association with orbital radiotherapy were evaluated in a small series of GO patients and the results compared with a ‘‘historical’’ group of patients previously treated with oral glucocorticoids and orbital radiotherapy (16). Favorable results were reported in the three groups, with no significant differences among them. In a subsequent randomized trial, the effect of IVIG was compared with that of oral prednisolone (17). The authors reported a similar percentage of successful treatments in the two groups. At variance in another study, no significant changes in ocular involvement occurred in the majority of patients treated by this procedure (18).

Antioxidants

Oxygen free radicals have been shown in vitro to stimulate proliferation of orbital fibroblasts and their expression of 72 kDa heat shock protein. In a nonrandomized, comparative study, two groups of 11 patients with mild-to-moderately severe ophthalmopathy were given either allopurinol (300 mg daily) and nicotinamide (300 mg daily), given for 3 months, or placebo. Improvement of ocular conditions occurred in 9 of 11 (82%) antioxidant-treated patients but only in 3 of 11 (27%) placebo-treated patients (p < 0.05) (19). This is the only one available study on the use of antioxidants for GO, and therefore it is premature to draw conclusions on their effectiveness. Larger, prospective, randomized studies are warranted to investigate this issue.

Cytokine Antagonists

Cytokines play an important role in the pathogenesis of GO and blockade of the cascade of events involving cytokines might play an important role in the management of GO, particularly in the early stage of the disease.

The only available data on the effects of cytokine antagonists in vivo on GO were reported by Balazs et al. (20) using pentoxifylline, a drug with complex immunomodulatory effects on cytokine production. In a nonrandomized and uncontrolled study, these authors treated 10 patients with

moderately severe GO with pentoxifylline (200 mg=day IV for 10 days, followed by 1800 mg=day orally for 4 weeks, and then reduced to 1200 mg=day until the end of a 3-month treatment) (20). Eight patients (80%) responded favorably. Soft tissue changes and proptosis were most responsive, whereas extraocular muscle involvement response was less impressive. Clearly, the results of this preliminary study must be interpreted with caution, and randomized and controlled studies are required to assess more accurately the true effectiveness of pentoxifylline.

Colchicine

Colchicine is an effective anti-inflammatory agent. A recent preliminary report on six GO patients has shown favorable results on soft tissue changes, and subjective symptoms (21). Since this study was uncontrolled, it is difficult to establish whether these changes are related to the natural history of the ophthalmopathy or to the effects of the drug.

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