Therapies for Graves’ Orbitopathy: IVMP and monoclonals, a breakdown of the evidence

Ruqaiyah Behranwala

Graves’ orbitopathy (GO), also called thyroid eye disease, is the most common extrathyroidal manifestation of Graves’ disease (1). The European Group on Graves’ Orbitopathy (EUGOGO) is an international, multidisciplinary scientific society with a goal of improving the care of patients with GO. It’s multicentric network contributes towards a better understanding of GO, its pathogenesis, newer therapies and their translation into clinical practice by carrying out large randomised controlled trials (RCT). Evidence-based data is combined to create treatment recommendations (2).

Current practice: The management of GO

Treatment relies on a thorough assessment of the activity and severity of GO and its impact on patient’s quality of life. Clinical assessment tools used include the Clinical Activity score (CAS), the EUGOGO scale and quality of life questionnaire (1). Patients are classified as having mild, moderate-to-severe, or sight threatening disease. In mild GO, a watchful strategy can be adopted using conservative measures such as topical lubricants and dark glasses, along with control of risk factors for disease progression, including smoking cessation and optimal thyroid disease control (2). Selenium supplementation has also been shown to improve mild manifestations and prevent progression to more severe disease (3).

The first line treatment for moderate-to-severe and active GO is high dose intravenous methylprednisolone (IVMP) in combination with mycophenolate sodium (4). The optimal cumulative dose of methylprednisolone appears to be 4.5-5g over 12 weeks. Higher doses up to 8g is used for sight threatening disease (2).

Second line treatment for moderate-to-severe active disease include a (i) second course of IVMP, (ii) oral glucocorticoids (GC) combined with cyclosporine or azathioprine, (iii) rituximab or teprotumumab or tocilizumab*. Orbital decompression surgery is needed in most patients once GO has been inactivated by immunosuppressive treatment (2).

* In this article, subsequent references to second-line treatment for moderate-to-severe active disease will refer to rituximab, teprotumumab, or tocilizumab.

There has been a significant uptake in the UK of EUGOGO’s first line treatment recommendations for moderate-to-severe active GO. However, uptake of second-line immunosuppression in clinical practice remains limited. A 2019 national survey reported that although 94% of respondents used IVMP as part of GO management, only 68% offered second-line immunosuppression when first-line intravenous steroid therapy failed within their own trust. (5) This may be because ophthalmologists have greater experience prescribing and monitoring steroid regimens compared with biologic therapies.

Limitations of current practice

Evidence suggests that the response rate to high-dose IVMP in severe cases ranges from 22% to 61%, highlighting that a substantial proportion of patients do not respond adequately, particularly with certain treatment protocols (6). 5% of patients may progress to sight-threatening optic neuropathy, requiring urgent intervention (7). 

Relapse rates also vary according to the IVMP dosage regimen. One study found that 11% of patients treated with medium-dose IVMP alone experienced recurrence, whereas the addition of agents such as mycophenolate mofetil reduced this risk to 8% (8). In contrast, a higher recurrence rate was reported with high-dose weekly IVMP for severe disease, with 26% of patients requiring reinitiation of IVMP after six months (9).

These findings indicate that, although IVMP remains the first-line treatment for active TED, a subset of patients require additional interventions such as second-line immunosuppressants or orbital decompression due to treatment resistance or disease relapse. In addition, prolonged high-dose steroid therapy over 12 weeks, requiring multiple hospital visits, can significantly affect patients’ quality of life. Potential complications include weight gain, infections, new onset or uncontrolled diabetes, hypertension, osteoporosis, psychosis, and, rarely, death (6).

Development of new therapies

Graves’ orbitopathy is an autoimmune condition in which antigen-presenting cells interact with TSH receptors on orbital fibroblasts, triggering infiltration of T and B cell infiltration and the release of pro-inflammatory cytokines, including interleukin 6 (IL-6). This stimulates the production of TSH receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) autoantibodies that target receptors on orbital fibroblasts, leading to glycosaminoglycan deposition, interstitial oedema and fat expansion (10).  The resulting myopathic, soft tissue, and eyelid changes reflects the active phase of the disease, which is often quantified using activity scores (2).

Corticosteroid therapy remains a cornerstone of GO management however, its efficacy is often limited by its nonspecific anti-inflammatory effects. In contrast, monoclonal therapies provide a targeted approach. Rituximab depletes B cells and reduces autoantibody production, teprotumumab inhibits IGF-1 receptor signalling on orbital fibroblasts, and tocilizumab blocks interleukin-6–mediated inflammatory pathways central to disease activity (2).

Rituximab

Meta-analyses have shown that rituximab significantly decreases CAS and TSH receptor antibody (TRAb) levels over time, but its effect on proptosis is generally limited or non-significant compared with baseline (11). In a RCT comparing rituximab with high-dose IVMP, rituximab showed greater CAS improvement at 16, 20, and 24 weeks. At 24 weeks, the overall response rate was 100% in patients treated with rituximab, compared with 69% in those receiving high-dose intravenous methylprednisolone (IVMP) (12). Patients treated with rituximab also had fewer disease reactivations, better eye motility outcomes and fewer required rehabilitative surgery. 

Rituximab is generally well tolerated, with most side effects being mild and infusion-related including transient pyrexia, hypotension, itching and headaches. Serious adverse events are less common but have been reported such as cytokine release syndrome and acute arthritis (12).

Teprotumumab

RCTs have demonstrated significantly higher overall response rates with teprotumumab compared with placebo in the treatment of active, moderate-to-severe GO, with marked improvements in both disease activity and proptosis. In the phase 2 and OPTIC phase 3 trials, 73% of patients treated with teprotumumab were overall responders, compared with 14% in the placebo groups (13,14). Achievement of a CAS 0–1 occurred in 62% of patients receiving teprotumumab versus 22% with placebo, while proptosis response was observed in 77% and 15% of patients, respectively, with improvements evident as early as week 6. Follow-up analyses demonstrated durable responses one year after treatment, with integrated proptosis, diplopia, and composite response rates of 67%, 69%, and 83%, respectively (15).

The most common adverse events reported with teprotumumab included muscle spasms, nausea, alopecia, diarrhoea, fatigue, hearing impairment, and hyperglycaemia (13,14).

Teprotumumab has received medicines and healthcare products regulatory agency (MHRA) approval for the treatment of adults with moderate-to-severe GO (16). However, NICE currently does not recommend its use, citing insufficient evidence to determine whether it provides a clinical benefit in this population.

Tocilizumab

In a randomised controlled trial of patients who failed initial glucocorticoid therapy, intravenous tocilizumab resulted in significantly greater reductions in CAS, with 86% of patients achieving CAS <3 compared with 35% in the placebo group at 16 weeks, with benefits predominantly affecting soft-tissue inflammatory signs (17). In a systematic review and meta-analysis comparing rituximab, tocilizumab, and teprotumumab in GO, tocilizumab showed the greatest reduction in CAS, followed closely by teprotumumab and then rituximab. Tocilizumab also significantly reduced TRAb levels more than rituximab, suggesting stronger effects on immunological markers in some studies. Overall, both tocilizumab and teprotumumab outperformed rituximab in reducing clinical activity and proptosis (18).

Tocilizumab is generally well tolerated however reported adverse effects include higher rates of infection due to neutropenia, headaches, thrombocytopenia, pruritic, weight gain, back pain, cellulitis and autoimmune hepatitis (17).

Conclusion

While IVMP remains the first line therapy for active, moderate-to-severe go, targeted monoclonal therapies offer a solution to variable steroid efficacy and steroid related morbidity. Teprotumumab shows the strongest evidence for improving disease activity and proptosis, while tocilizumab is particularly effective in suppressing inflammatory activity; rituximab may benefit selected patients. Future clinical practice may increasingly shift towards monoclonal therapies as high-quality studies define optimal patient selection and long-term outcomes.

References

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