15th International Thyroid Congress, 85th Annual Meeting of the American Thyroid Association:

IV Steroids for the Treatment of Clinically Active and Severe Obitopathy in Graves’ Disease

Presented at the meeting by George J. Kahaly, MD, PhD

In the upcoming guidelines of the European Thyroid Association (ETA) and the European Group on Graves’ Orbitopathy (EUGOGO), intravenous corticosteroids are indicated at every stage of the eye disease, and specifically for treatment of clinically moderate-to-severe and active orbitopathy, George J. Kahaly, MD, PhD, explained at the 15th International Thyroid Congress and 85th Annual Meeting of the American Thyroid Association (ITC/ATA).

The updated EUGOGO guidelines are slated to publish in the December 2015 issue of the European Thyroid Journal.

eye, eye ball, orbit

The goals of intravenous corticosteroid treatment for Graves’ orbitopathy are to reduce orbital pain, improve functional biomarkers, improve appearance, preserve and/or restore visual acuity, prevent complications, and shorten the active phase of this autoimmune disorder, said Dr. Kahaly, who is Professor of Medicine and Endocrinology/Metabolism at the Johannes Gutenberg University Medical Center, Mainz, Germany.

Intravenous steroids are more effective and have a lower side effects burden than oral steroids and, thus, are the preferred mode of administration. Successful treatment outcome has been demonstrated in 83% of patients treated with 500 mg methylprednisolone for 4 cycles at 4 weekly intervals compared with 11% of patients receiving placebo (P=0.005), Dr. Kahaly explained.1

“If the first course of intravenous steroid is unsuccessful—and this happens in 15% to 20% of cases—you may start a second course after a few weeks interval,” Dr. Kahaly said.

How to Treat Graves’ Orbitopathy with Intravenous Steroids
“Corticosteroids activate the transcription of antiinflammatory mediators and inhibit the transcription of proinflammatory mediators (ie, cytokines and prostaglandins),” Dr. Kahaly said. Intravenous steroids suppress the immune system in two ways: through a genomic pathway that determines long-term effects and through a non-genomic pathway that takes effect within a few seconds to minutes of use.  

In patients with Graves’ disease, pro-inflammatory cytokines stimulate the enzyme 11-beta hydroxysteroid dehydrogenase 1 (11beta-HSD1), which enhances the generation of cortisol that leads to maturation of adipocytes and increased adipogenesis, Dr. Kahaly explained. “Intravenous steroids inhibit the activation of this key enzyme, lowering the concentration of cortisol and inhibiting orbital adipogenesis,” he explained.  

Furthermore, proteome analysis of orbital tissue shows upregulation of numerous pro-inflammatory proteins in patients with untreated severe Graves’ orbitopathy compared to control patients without eye disease, according to a study by Dr. Kahaly and colleagues.2 The study also showed that “intravenous steroids markedly decrease the upregulation of the inflammatory proteins in orbital tissue of untreated patients with severe disease, and that smoking attenuates this effect,” Dr. Kahaly said.

Thus, the EUGOGO guidelines recommend high-dose intravenous steroids as first-line treatment for moderate-to-severe and active orbitopathy and that treatment should be administered in centers with appropriate expertise given the risk for treatment-related complications, Dr. Kahaly said. For example, patients should first be screened for contraindications to intravenous corticosteroids, including liver dysfunction, recent viral hepatitis, severe cardiovascular morbidity, uncontrolled hypertension, and unstable diabetes.

Recommended Dosing Regimen
Based on evidence-based studies showing greater treatment-related morbidity and mortality with higher doses, particularly cumulative doses exceeding 8 g, the EUGOGO recommends that the cumulative dose of intravenous steroids should not exceed 8 grams in one course of therapy. For patients with inflammation only, 0.5 g per day once weekly with a cumulative dose of 4.5 g over 12 weeks is preferred. For patients with severe eye disease and constant diplopia, a higher dose of 0.75 g with a cumulative dose of 7.5 gm over 12 weeks may be required, Dr. Kahaly said.

Concluding Remarks
When treating patients with intravenous steroids, the first step is to make sure that the patients do not have contraindications including hepatitis and liver dysfunction, Dr. Kahaly said. Physicians should tailor the dose according to the severity and activity of the disease, with the cumulative dose not exceeding 8 g.

 

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