Update on Graves Disease

Advances in Treatment of Mild, Moderate and Severe Thyroid Eye Disease

Diego Strianese


Curr Opin Ophthalmol. 2017;28(5):505-513. 

In This Article

New Therapeutic Advances for Moderate-to-severe) Thyroid Eye Disease

Patients in the 'moderate-to-severe' category have symptoms that are not sight-threatening but have sufficient impact to justify immunosuppression and/or surgery.[9] Systemic steroids are the mainstay of medical treatment for active, moderate-to-severe TED. Pulses of intravenous steroids are superior to continuous oral steroids both in terms of efficacy and a more favorable side-effect profile.[14] The optimal intravenous methylprednisolone regimen for moderate-to-severe TED is weekly doses of 500 mg for 6 weeks followed by 250 mg for a further 6 weeks. However, relapse after completion of treatment is approximately 20% and CON develops in 7.5% of patients.[15] Cumulative doses of methylprednisolone exceeding 8 g have been associated with acute hepatic failure and this threshold (or equivalent for other glucocorticoids) should not generally be exceeded.[16]

The combination of steroid and RT seems to be effective in long term;[17] however, studies must take into account the known tendency of TED to improve spontaneously with time. A retrospective study of 226 patients investigated the impact of associated/additional treatments and other variables on Graves' orbitopathy outcomes after intravenous glucocorticoids. Overall, Graves' orbitopathy improved in approximately 60% of patients (responders), whereas it was stable or worsened in approximately 40% of patients (nonresponders). The outcomes of eyelid aperture, CAS and diplopia correlated with time between the first and last observation. The outcomes of proptosis, eyelid aperture and visual acuity correlated with orbital decompression. The outcome of diplopia correlated with orbital RT. The authors concluded that their findings confirmed that time (the natural history of Graves' orbitopathy) is a key factor in determining the long-term outcome of Graves' orbitopathy.[18]

The use of steroids has a number of implications.[14] Side-effects may require the withdrawal of therapy and the need to remain below a certain safe threshold of the overall amount given has prompted investigators to find adjuvant or alternative therapies. RT combined with steroid treatment, either administered systemically or locally by retrobulbar injection, showed significantly greater efficacy, particularly on ocular motility.[19] In a recent study, 35 consecutive patients with active moderate-to-severe TED with contraindications to steroid therapy received bilateral retrobulbar irradiation (total dose of 20 Gy). Seven-point CAS (7-CAS), ocular motility, visual acuity, exophthalmos and eyelid retraction were evaluated at 3, 6 and 12 months. There was a statistically significant improvement in 7-CAS at 3, 6 and 12 months (P < 0.05). Ocular motility disturbances improved at 6 and 12 months (P < 0.05). Visual acuity remained stable; there was no significant change in exophthalmos or eyelid retraction The authors concluded that RT alone should be considered in moderate-to-severe TED, particularly to reduce periocular inflammatory changes and motility disruption, but not for lid retraction or proptosis.[20] However, additional reports of RT for TED showed success from 20 to 80%. Reasons for this variation include heterogeneous patient populations, patient selection bias and differing concomitant therapy.[17,18,20]

In assessing steroid-sparing agents, azathioprine has not been shown to be of benefit as a single agent.[21] but exhibits effectiveness when combined with radiation therapy or steroids.[22,23] Methotrexate has been show to be effective as a sole treatment in patients who fail steroids or became steroid dependent. Two recent studies confirmed that methotrexate provides a steroid-sparing effect in a subset of patients with TED; weekly dose varied from 5 to 20 mg. In the most recent report, 14 patients with TED who were unable to discontinue prednisone therapy without disease recurrence were included. Patients received methotrexate (15 mg/week orally or 20 mg/week subcutaneously). Five patients discontinued therapy for a lack of benefit or intolerance. Of the nine patients who remained on methotrexate, all were able to discontinue prednisone completely after an average duration of 7.5 months. Improved visual acuity and partial improvement in ocular motility was achieved in seven and five patients, respectively. In a previous study, methotrexathe was used in 36 consecutive patients with recurrent active TED, previously treated with corticosteroids, stopped because of side effects. Two different weekly doses were administered depending on the weight of the patient (7.5 or 10 mg). There was a statistically significant improvement in 7-CAS at 12 months after treatment (P < 0.0001). There was no significant change in visual acuity. Ocular motility disturbances improved significantly at 12 months (P < 0.001). There was no significant change in exophthalmos or eyelid position.[24,25]

Mycophenolate mofetil (MMF) is a immune modulatory drug which inhibits the inosine monophosphate dehydrogenase, leading to inhibition of the de-novo pathway for guanosine monophosphate synthesis, resulting in depletion of the pool of guanosine-tri-phosphate and thereby inhibiting the proliferation of lymphocytes. Recently, a study was published on 74 patients with active moderate-to-severe TED who were randomized to receive either MMF or glucocorticoids. MMF group therapy showed a better CAS response than glucocorticoid one (92.5 vs. 70.5% improved, P < 0.05) and a significantly improved rate of diplopia and proptosis at the 24th week (90.4 and 68.8%, respectively). Disease reactivation was not observed in the patients treated with MMF but was observed in patients after glucocorticoid therapy. Adverse events occurred in 5% of patients treated with MMF which were mild to moderate related to increased risk of infection.[26]

In recent years, many reports have shown the effectiveness of the biological agents for TED. The most commonly studied biologic agent in TED is rituximab (RTX), an anti-CD20 monoclonal antibody that targets CD20 on B cells and its precursors.[27] A RCT in Europe comparing RTX with intravenous methylprednisolone in active moderate–severe TED supports effectiveness and disease-modifying effects with a 100% response rate, no reactivation of TED at 24 weeks and less rehabilitative surgery required at 76 weeks.[28] A controlled trial in North America comparing RTX with placebo did not show a significant difference in the improvement of disease activity at 24 and 52 weeks, and there were more moderate-to-severe adverse events in the RTX group.[29] The conflicting results from the RTX RCTs could be related to small sample sizes, requiring clarification with larger controlled studies.[27]

Tocilizumab, a recombinant humanized monoclonal antibody to the interleukin-6 receptor, used in the treatment of severe rheumatoid arthritis and juvenile idiopathic arthritis, has been evaluated in 18 patients with active TED refractory to intravenous steroids. Tocilizumab significantly improved CAS in all patients and disease activity remained stable up to 27 months after infusion, improved proptosis in 72%, extraocular motility in 83% and diplopia in 54% of patients[30]

Etanercept, a tumor necrosis factor (TNF) receptor blocker, improved the CAS significantly in 10 consecutive patients suffering from mild-to-moderate TED; however, 30% had recurrence of TED activity after treatment cessation.[31] Adalimumab, a fully human monoclonal antibody against TNF, may control prominent inflammatory symptoms in TED patients[32]

A multicenter, double-masked, randomized, placebo-controlled trial has been recently published to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe TED. The primary end point was defined as a reduction of 2 points or more in the CAS and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, CAS and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Sixty-nine percent of patients who received teprotumumab as compared with 20% patients who received placebo had a response at week 24 (P < 0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes. The authors concluded that a 24-week course of teprotumumab therapy provided clinical benefit in patients with active, moderate-to-severe TED by reducing proptosis, CAS and improving the patients' QoL.[33]