Plastics, Oncology, Uveitis Landmark Studies

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Can you predict which patients with Thyroid Eye Disease will respond to immunosuppressive treatment? In this 1997 study, patients with Graves’ Ophthalmopathy were assessed using the Clinical Activity Score (CAS) and treated with oral prednisone (n = 22) or retrobulbar irradiation (n = 21) and graded on their response to treatment based on the CAS.

Key Points:

• There was no statistical difference in outcomes between the treatment modalities 
• The pretreatment CAS was significantly higher in responders than in non-responders. 12/22 responders and 3/21 non-responders had a CAS > 4 (55% vs 14%; P < 0.01). 
• Using CAS of 4 as cut-off point, the accuracy of CAS in predicting the therapeutic outcome was: specificity 86%, sensitivity 55%, positive predictive value 80%, negative predictive value 64%.

Overall, the CAS Graves’ Ophthalmopathy study is a landmark study because it offered an easy, inexpensive, and entirely clinical score that providers can use to predict which patients are more likely to respond to immunosuppressive therapy. These data can be used to assist clinical decision-making and patient satisfaction in the treatment of Thyroid Eye Disease.

Do doctors need to suppress the use of immunosuppressants? Corticosteroids had been the mainstay of treatment for patients with severe ocular inflammatory disease despite the known side effects. Many ophthalmologists were resistant to using other types of systemic due to concern for increased risk of malignancy. The retrospective cohort SITE study sought to determine if the use of immunosuppressants for the treatment of severe ocular inflammatory disease had a higher risk of development of malignancy than conventional therapy with corticosteroids.

Key Point:

• The rates of malignancy development between patients treated with corticosteroids (1/207), immunosuppressants after initial treatment with corticosteroids (2/189), and immunosuppressants alone (2/141) were not statistically different (P = 0.35).

This study concluded that the rate of developing malignancy in patients with severe ocular inflammatory disease treated with immunosuppressants was no different than those patients treated with corticosteroids alone. Their results support substituting immunosuppressants for corticosteroids in the treatment of these patients since the latter have become increasingly ineffective and chronic use causes highly unfavorable side-effects.

Now that you see it, what do you do with it? The COMS was a prospective multicenter trial organized by the National Eye Institute in 1985 to examine mortality outcomes of different treatment options for uveal melanoma. They also examined cancer free survival, metastasis free survival, and years of functional vision. There were three main arms of the study, which differentiated melanomas based upon tumor size. It is important to note that this study is not applicable to melanomas of the ciliary body or peripapillary choroid.

Small tumor trial (1mm < height <3mm and 5mm < diameter < 16mm)

• Objective: do these patients need treatment?
• Methods: observational study with a smaller (N = 188)
• Result: mortality is low for small melanomas, tumor grows slowly
• Takeaway: small choroidal melanomas can be observed safely 

Medium tumor trial (2.5mm < height < 10mm and diameter <16mm)

• Objective: do these eyes need enucleation?
• Methods: randomized to enucleation (N = 660) vs. plaque brachytherapy with i125 (N = 657)
• Result: no difference in mortality outcomes at 5 years (enucleation = 81%, plaque = 82%, p = 0.48) so both are options
• Takeaway: plaque brachytherapy is a viable option for medium sized melanomas, long-term data for brachytherapy survival is still pending

Large tumor trial (height > 8mm and/or diameter > 16mm)

• Objective: does radiation improve mortality?
• Methods: randomized to enucleation alone (N = 506) vs. external beam radiation therapy (20 Gy) followed by enucleation (N = 497)
• Result: no difference in mortality outcomes at 5 years (57% enucleation, 62% EBRT then enucleation) or 10 years (40% enucleation, 45% EBRT then enucleation)
• Takeaway: pre-enucleation radiotherapy is no longer used as it is ineffective 

The COMS is a landmark study because it helped guide physicians on when and how to treat ocular melanomas, which are the most common primary eye tumors in adults. Although nonmalignant choroidal nevi are more common than choroidal melanomas, all nevi should be evaluated for features concerning for melanoma as choroidal melanomas have high mortality rates.

Do you really count each individual cell in the anterior chamber? While some may not always count each cell, there is a reason you might have to. Prior to the Standardization of Uveitis Nomenclature workshop, the classification and grading of uveitis was not entirely clear. In order to make a more standardized system, 45 experts were included in a workshop, which had the goal of defining terminology, grading, and ways to report outcomes for uveitis.

Key Points:  

• Anatomic classification by primary site of inflammation was the key factor: anterior, intermediate, posterior, and panuveitis
• Clinical course has a variety of factors to consider including: onset, duration, and recurrence
• A set of guidelines for grading cell and flare per high power field (1x1 mm) were created 

Overall, the SUN workshop was not quite a landmark study, but instead the basis for clinically characterizing uveitis, which is why it is important for a variety of other studies in addition to clinical practice.

What must you do to effectively treat noninfectious uveitis? In the 2011 MUST trial, patients with noninfectious intermediate, posterior, or panuveitis from 23 centers were randomized to fluocinolone acetonide implant therapy (n = 129) or systemic therapy (n = 126) with two-year follow-up. 

Key Points:

• Both implant (+6.0 letters) and systemic therapy (+3.2 letters) improved mean visual acuity over 24 months, though the difference was not found to be statistically significant (P = 0.16)
• Residual active uveitis decreased to 12% for implant therapy and 29% for systemic therapy (P = 0.001) at 24 months follow-up
• Vision-related quality of life improved for both treatment groups

The MUST trial highlights the effectiveness of both forms of anti-inflammatory corticosteroid-based therapies for noninfectious uveitis. This is a landmark study as neither approach was determined to be superior to the other, allowing for choice of treatment to be based on pros and cons specific to a patient’s individual clinical circumstances.

 Treating uveitic macular edema? This study will POINT you in the right direction. Before the POINT trial, commonly used therapeutics for uveitic macular edema had not been directly compared, with literature supporting the efficacy of each. In the 2019 multicenter POINT clinical trial, the efficacy of periocular triamcinolone acetonide (PTA, n=73), intravitreal triamcinolone (ITA, n=79) and intravitreal dexamethasone implant (IDI, n=78) for treatment of uveitic macular edema were compared. 

Key Points:

• ITA and IDI groups had BCVA improvement 5 letters greater than the PTA group at 8 weeks (p<0.004)
• IDI and ITA were superior to PTA in improving and/or resolving uveitic macular edema
• Risk of IOP ≥ 24 mmHg was higher in the intravitreal groups compared to the periocular      group: hazard ratio (HR) 1.83 for ITA, 2.52 for IDI

Overall, the POINT trial found intravitreal corticosteroid treatments (ITA and IDI) to be better therapeutic agents than periocular corticosteroids (PTA) for uveitic macular edema. However, rates of increased IOP were greater in the ITA and IDA groups.