Is Radioactive Iodine Contraindicated in Patients with Moderate-to-Severe and Active Graves’ Orbitopathy?

Management of Graves’ hyperthyroidism in patients with associated Graves’ orbitopathy (GO) is a challenging dilemma in the absence of randomized clinical trials specifically addressing this issue. Graves’ hyperthyroidism can be managed by nonablative antithyroid drug (ATD) treatment or by ablative treatments, i.e., radioactive iodine (RAI) or total thyroidectomy. Neither treatment is perfect, since ATD withdrawal is frequently followed by a relapse of hyperthyroidism, while RAI and thyroidectomy almost invariably (and deliberately) cause permanent hypothyroidism and the need for lifelong levothyroxine replacement. In a recent, large international survey among specialists, ATDs were indicated as the first-line treatment for uncomplicated Graves’ hyperthyroidism by the vast majority of participants, while RAI and, to a greater extent, thyroidectomy were far less popular. ¹ In general, any treatment can be used in uncomplicated Graves’ hyperthyroidism, based on standardized criteria and patient preference following a shared decision-making process.

The choice of treatment is more complex if Graves’ disease is complicated by GO, particularly if the latter is moderate-to-severe and active. Clinical practice guidelines developed by the European Group on Graves’ Orbitopathy (EUGOGO) state that in these cases (about 10% of patients with Graves’ disease), RAI should be avoided due to the potential RAI-associated progression of GO. ² A similar recommendation is expressed in the American Thyroid Association and the European Thyroid Association consensus statement. ³ However, the evidence concerning this untoward effect of RAI relates to patients with absent or mild GO, ⁴ not to patients with moderate-to-severe and active GO.

In the current issue of Thyroid, Cosentino et al. ⁵ report the results of a retrospective cohort study in which 49 patients with Graves’ disease complicated by moderate-to-severe and active GO were treated for hyperthyroidism by either ATDs or RAI shortly followed by intravenous glucocorticoid treatment (12 weekly infusions, starting 2 weeks after RAI administration) for GO. The primary endpoint (overall outcome of GO at 24 weeks) was significantly better in the RAI group (54% responders) than in the ATD group (16% responders), although differences in the response rate between the two groups became insignificant at the last visit at 72 weeks (62% responders in the RAI group, 52% in the ATD group). ⁵ Improvement in the quality of life followed the same trend. Most importantly, progression of GO at 24 weeks occurred in only one patient (4%) in the RAI group vs. three patients (12%) in the ATD group. ⁵ Although this study bears the limitations of a retrospective design, its results, which showed at least a similar risk of progression of moderate-to-severe and active GO after RAI therapy or during ATD treatment, suggest that RAI should not be banned in patients with moderate-to-severe and active GO if treatment with intravenous glucocorticoids is concomitantly carried out.

This is the same conclusion reached by a recent mini-review by Bartalena & Smith ⁶ following reevaluation of the results of three randomized clinical trials (RCTs). In an RCT of 82 Graves’ patients whose moderate-to-severe and active GO was treated by orbital radiotherapy combined with either oral or intravenous high-dose glucocorticoids, all patients received RAI treatment 1 week before starting therapy for GO. ⁷ Progression of GO occurred in two patients in the oral glucocorticoid group, but in no patient in the intravenous glucocorticoid group. ⁷ A second RCT of 60 patients in whom GO was treated by intravenous glucocorticoid monotherapy, hyperthyroidism was managed by total thyroidectomy alone, or thyroidectomy followed by RAI 2 weeks before initiating treatment for GO. ⁸ Three patients submitted to thyroidectomy alone and two patients treated by total thyroid ablation had some exacerbation of GO at 3 months, but at 9 months no patient in the total thyroid ablation group manifested GO progression compared to baseline. ⁸ Finally, in a third RCT of 40 patients, hyperthyroidism was treated by either total thyroidectomy alone or thyroidectomy followed by RAI prior to intravenous glucocorticoid treatment for moderate-to-severe and active GO. ⁹ While in the group treated only by surgery, GO progressed in two patients at 6 months and three patients at 12 months, no progression of GO was observed at 3, 6, and 12 months in the group treated by thyroidectomy followed by RAI. ⁹

ATD treatment, possibly long-term, remains in clinical practice the preferred thyroid treatment in patients with moderate-to-severe and active GO. ² However, based on the paper by Cosentino et al. ⁵ and the reevaluation of previous data from the literature, ⁶ we suggest that, if selected on the basis of standard criteria and the preference of the informed patient, RAI can be safely used to treat hyperthyroidism both in patients with mild GO and in those with moderate-to-severe and active GO. In the former, the use of RAI should be accompanied, under most circumstances, by relatively low-dose prednisone prophylaxis (0.1–0.2 mg body weight gradually tapered and withdrawn after 6 weeks) to prevent possible RAI-associated progression of GO. ⁴ In the latter, RAI administration should be rapidly followed by high-dose anti-inflammatory/immunosuppressive therapy for GO, as well as by a strict follow-up of thyroid function to promptly correct post-RAI hypothyroidism. ¹⁰ Whether teprotumumab has a similar effect in patients receiving RAI treatment is presently unknown. In addition, what remains unsettled is whether thyroid ablation, either by RAI, thyroidectomy, or a combination of the two treatments, is superior to the conservative approach or vice versa in terms of long-term outcome of GO. This question can only be answered by large, multicenter, randomized clinical trials.