Uveitis Metrics: With Standardization, Treatment Protocols Can Improve

Uveitis encompasses a diverse spectrum of disease syndromes with varying etiologies and disease presentations. Because of this heterogeneity of conditions, comprehensive guidelines for uveitis diagnosis assessment and evaluation across all diseases are difficult to establish. However, more objective disease grading standards can improve how physicians treat the various subtypes and monitor response to therapies.

The field of uveitis has benefited from prior working groups to classify uveitis syndromes on the basis of anatomic location. The Standardization of Uveitis Nomenclature (SUN) Working Group provided guidance for anatomic classification of uveitis with a considered emphasis on rigorous clinical grading of anterior chamber cell and vitreous cell and haze based on cell counts with specific biomicroscopic techniques. 

With these clinical benchmarks available to the ophthalmologist in clinical practice and in clinical research, the importance of ocular imaging standards has been increasingly recognized by the National Eye Institute (NEI), the US Food and Drug Administration (FDA), and the Office of National Coordinator (ONC). A joint workshop on Promoting the Adoption of Ocular Imaging Standards was held in 2022 to promote discussion of knowledge gaps, barriers, and strategies to achieve this goal.¹ 

The work of these investigators shows that, while a precise consensus is still in the works, ophthalmology is likely already working with the technologies that will make it possible to develop clear, yet circumspect metrics across uveitis subtypes.

Objective Metrics of Inflammation: Applicable for All Categories and Subtypes of Uveitis

While infectious and noninfectious uveitis syndromes differ in their diagnostic workup and management, the assessment of both involves inflammation grading that may require clinical and photographic grading during follow-up.

Several grading systems have been developed to evaluate intraocular inflammatory markers of uveitis, including anterior chamber (AC) cell, AC flare, vitreous cell, and vitreous haze. However, the existence of the differences in their grading schemes that rely on clinician or investigator interpretation (e.g., anterior chamber cell counts and vitreous haze via indirect ophthalmoscopy) may lead to reduced reproducibility and may be subject to limitations related to the underlying disease state (e.g., posterior synechiae and pupillary constriction may lead to difficulty grading vitreous haze). 

Uveitis Standardization Will Enhance Accuracy

The SUN Working Group provides foundational guidance related to inflammation grading schema and classification criteria. The goals of the group include improvement of research comparability across different physicians and investigators to more accurately characterize the clinical progression of disease with an international set of standards for clinical data in uveitis.^1,2 

Ophthalmic imaging techniques have become increasingly available and may improve the accuracy of reported data in both clinical practice and research. These modalities include fundus photography, fundus autofluorescence, optical coherence tomography (OCT) and other novel imaging modalities, as well as emerging evidence supporting artificial intelligence-based assessment.

Disease-specific uveitis metrics given the heterogeneous nature of uveitis have also emerged as a method to objectively assess active and inactive uveitis. The use of standardized imaging techniques and endpoints will enhance the accuracy and reliability of clinical trials in uveitis, with the ultimate goal of improved patient outcomes assessments of efficacy in the reduction of inflammation and structural complications associated with uveitis (e.g., uveitic macular edema). 

Hypothesized benefits include facilitated transfer of images and encouragement of interoperability and collaboration between providers. Additionally, artificial intelligence techniques could be applied to screen ophthalmic conditions and leverage analysis of large volumes of data, enabling more precise diagnoses and treatments. Use of the Digital Imaging and Communications in Medicine (DICOM), the international standard for medical images and related information, in the setting of ophthalmic imaging is currently optional and not widespread.³ This workshop renewed the commitment to DICOM implementation to improve coherence of how ophthalmic imaging results are utilized. By establishing a set of standards for ocular imaging, researchers and clinicians will be able to more easily collaborate, compare results, and develop more effective treatments for ocular diseases.

Trials Show Objective Uveitis Metrics at Work

Ophthalmic metrics used in prior landmark studies include grading of vitreous haze, anterior vitreous cells, and other markers for inflammation to determine the severity of uveitis. One grading methodology is the Nussenblatt scale, which is regarded by the SUN working group as the standard for measuring vitreous inflammation.¹ This method uses indirect ophthalmoscope examination and comparison of the findings to standardized fundus photos with different degrees of vitreous haze.⁴ However, there are multiple limitations to clinician grading, including poor discrimination, low sensitivity, and suboptimal interobserver agreement.⁵ Anatomic factors such as presence of a cataract, media opacity, and synechiae can also impede the ability to accurately grade vitreous haze. The Efficacy and Safety of Adalimumab in Patients With Active Uveitis (VISUAL I) trial (ClinicalTrials.gov Identifier: NCT01138657) studying adalimumab in patients with active noninfectious uveitis used outcomes such as change in AC cell and vitreous haze grade.⁶ These parameters were assessed and graded during exam in accordance with SUN criteria. 

In recent years, objective measures to characterize uveitis using OCT imaging have been developed. Benefits of this modality include improved visualization of vitreous inflammatory cells and quantitative assessment of image parameters.⁷ With the advancement of imaging technology, use of these objective imaging measures would be instrumental in clinical trials. Uveitis-related trials, such as the Multicenter Uveitis Steroid Treatment (MUST) Trial (ClinicalTrials.gov Identifier: NCT00132691) and Adalimumab vs. Conventional Immunosuppression for Uveitis (ADVISE) ADVISE trial (ClinicalTrials.gov Identifier: NCT03828019) have integrated ophthalmic imaging grading into metrics of disease activity, including fundus photography, OCT, and fluorescein angiography (FA), particularly for posterior segment uveitis.

More clinical trials have incorporated image-related metrics into their study endpoints. 

The Suprachoroidal Injection of CLS-TA in Subjects With Macular Edema Associated With Non-infectious Uveitis (PEACHTREE) study (ClinicalTrials.gov Identifier: NCT02595398)

 that examined suprachoroidal triamcinolone acetonide as a treatment for macular edema associated with non-infectious uveitis utilized visual acuity improvement as the primary endpoint and central subfield thickness (CST) measured by spectral-domain OCT as a key secondary endpoint. This clinical trial differed from other uveitis registration trials where vitreous haze was utilized as the primary endpoint. The study to Investigate RO7200220 in Participants With Uveitic Macular Edema (Meerkat, ClinicalTrials.gov Identifier: NCT05642312), an investigation of the efficacy of anti-IL-6 immunoglobulin RO7200220 in participants with uveitic macular edema, is assessing the proportion of participants with resolution of macular edema as defined by a standardized CST threshold on OCT. This trend demonstrates increasing use of image-based uveitis metrics, such as CST as measured by OCT, and other algorithms based on reading-center determined assessments.

Disease-Specific Metrics Can Aid Imaging for Care and Research

In addition to the established criteria for assessing inflammation, different pathologies may require evaluation of alternative disease-specific metrics. The ADVISE study, which is ongoing, is comparing adalimumab, an anti-TNF-α monoclonal antibody, to conventional immunosuppression for uveitis. Disease-specific metrics for clinical and imaging findings are being utilized to determine uveitis activity, and imaging techniques to assess the choroid and retina will be used to assess posterior segment inflammation. For example, OCT remains the imaging modality of choice for exudative retinal detachments and macular edema, while fundus autofluorescence is preferred for evaluation of choroidal inflammatory lesions (e.g., multifocal choroiditis, serpiginous choroidopathy). Fluorescein angiography is used to assess for vascular leakage and sheathing seen in retinal vascular inflammation (e.g., isolated retinal vasculitis and panuveitis with retinal vasculitis).⁸

Ophthalmic imaging has become an increasingly important tool in addition to the established standardization of uveitis classification criteria for clinical grading. Imaging in uveitis metrics allow for objective measures to characterize the disease at baseline evaluation, provides valuable information in conjunction with clinical grading schemes, and enables clinicians to accurately monitor disease activity. With the growing need for precise and standardized measures in clinical research, the integration of ophthalmic imaging techniques such as OCT, fundus autofluorescence, and FA metrics can help to establish reliable and consistent endpoints. Implementation of ophthalmic imaging standards can reduce variability and increase accuracy, leading to better patient outcomes assessment and improved quality of care. The continued development and refinement of ophthalmic imaging techniques will undoubtedly play a critical role in advancing our understanding and management of uveitis.

Dr Huang is an alumnus of University of Pennsylvania and recently graduated with Distinction from the University of Nebraska Medical Center, College of Medicine. Dr Huang will be an Ophthalmology Resident at the Illinois Eye and Ear Infirmary, University of Illinois Chicago.

Dr Yeh is currently professor and Stanley Truhlsen, Jr. Chair in Ophthalmology at the Truhlsen Eye Institute, University of Nebraska Medical Center. His fields of clinical care and research include uveitis, vitreoretinal surgery and global ophthalmic health.