The double-edged sword of inflammation in inherited retinal degenerations: Clinical and preclinical evidence for mechanistically and prognostically impactful but treatable complications

Frontiers in Cell and Developmental Biology · 3 authors, 1 centre

AI SUMMARY

FIDELITY 100%

POPULATIONPatients referred for possible IRD who exhibited inflammatory signs and underwent autoantibody testing between 2016 and 2022 at the Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases

INTERVENTIONDetection and characterization of anti-retinal and anti-optic nerve autoantibodies by Western blot and retinal immunohistochemistry; treatment (where applicable) with intravitreal and/or sub-Tenon steroid injections and/or immunomodulatory therapy (e.g., mycophenolate mofetil)

COMPARISONNo direct control group; comparison of visual function and imaging findings before and after treatment in select cases; comparison with historical natural history controls for thymopentin pilot trial

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This retrospective study of 418 patients found that secondary autoimmune inflammation is common in inherited retinal degenerations (IRDs), particularly in certain genotypes like EYS and USH2A, and is associated with anti-retinal and anti-optic nerve autoantibodies. Treatment with steroids and immunomodulatory therapy led to measurable improvements in visual function, including visual field restoration, in many patients. The findings highlight that inflammation in IRDs is not merely an epiphenomenon but a treatable complication that can significantly impact prognosis and should be actively managed.

Full summary

5,135 CHARS

**Background** Inherited retinal degenerations (IRDs) are a genetically heterogeneous group of disorders characterized by progressive photoreceptor degeneration and vision loss. The role of inflammation in IRDs has been noted since early descriptions, with cystoid macular edema (CME) being a well-known complication. However, the presence and clinical relevance of a broader inflammatory component, including optic nerve involvement and systemic autoantibodies, has been debated. This study aimed to characterize anti-retinal (AR-AAb) and anti-optic nerve (AON-AAb) autoantibodies in a cohort of IRD patients with inflammatory signs, assess genotype-specific associations, and evaluate the response of these inflammatory complications to immunomodulatory treatment.

**Methods** A retrospective review was conducted of 418 subjects seen at the Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases between 2016 and 2022 who exhibited signs of inflammation (criteria including absence of waxy pallor, disc hyperemia, thickened RNFL on OCT, late leakage on IVFA, CME, etc.) and underwent CLIA-certified testing for AR-AAbs and AON-AAbs by Western blot and retinal immunohistochemistry (rIHC). Among these, 127 had a molecularly confirmed IRD. In addition, records of 515 patients with disease-causing mutations in genes commonly associated with inflammation were reviewed for within-gene frequency of AAb positivity. Detailed subgroup analyses were performed for EYS (n=20) and USH2A (n=75) mutation carriers. Three representative cases (RHO P23H, EYS, ABCA4) are presented with detailed pre- and post-treatment assessments including visual fields (VF), ffERG, SD-OCT, IVFA, and autoantibody profiles.

**Key Results** - Of 418 AAb-positive subjects, 127 (30.3%) had a confirmed IRD; 261 had primary autoimmune retinopathy/optic neuropathy or paraneoplastic forms. Nine additional IRD subjects with suspected inflammation tested negative for AAbs and rIHC. - Genotypes most frequently associated with AAb positivity included EYS, USH2A, MERTK, CRB1, BBS1, NR2E3, ABCA4, RHO, RP1, KLHL7, and PRPF family genes (especially PRPF31). Within-gene frequency was very high for some rare genes (e.g., 100% for MERTK and KLHL7 in this cohort). - In EYS patients (n=20): 70% (14/20) exhibited subclinical inflammation. Of those tested, AR-AAbs were found in 11/12 (most common: anti-enolase 8/12, anti-TULP1 4/12), AON-AAbs in 8/9 tested, and positive rIHC in 9/12 (predominantly photoreceptor staining). IVFA revealed optic nerve leakage in 19/24 eyes, vascular leakage in 14/24 eyes, and combined leakage in 11/24 eyes. RNFL thickening was seen in 24/26 eyes. Treatment with steroids led to subjective and measurable vision improvements. - In USH2A patients (n=75): 66.7% (50/75) had subclinical inflammation. AR-AAbs were found in 32/35 tested (most common: anti-carbonic anhydrase II 16/35, anti-enolase 15/35), AON-AAbs in 28/34 tested, and positive rIHC in 28/34 (photoreceptor staining 26/34). IVFA showed leakage in 38/62 eyes. RNFL thickening in 49/80 eyes. CME was present in 47/150 eyes (31%). Treatment (steroids ± IMT) resulted in improved vision in most. - Three illustrative cases: 1. RHO P23H ADRP: A 51-year-old female with altitudinal RP but concentric VF constriction, disc leakage on IVFA, and RNFL swelling on OCT. After 3 years of subtenon triamcinolone, VF fully restored to expected altitudinal defect. 2. EYS ARRP: A 28-year-old female with CME and optic nerve inflammation. After intravitreal/subtenon steroids and oral mycophenolate mofetil (MMF), VF widened and CME resolved/reduced at 2 years. 3. ABCA4 CORD: A 29-year-old male with sudden vision loss to light perception. After treatment with intravitreal triamcinolone and MMF, BCVA recovered to 20/200 and FST improved by 3.5–4.5 log units.

**Clinical Implications** This study provides strong evidence that secondary autoimmune inflammation is a common and clinically significant complication in many IRD genotypes, often involving both retinal and optic nerve components. The presence of AR-AAbs and AON-AAbs correlates with imaging findings (e.g., IVFA leakage, RNFL thickening) and, importantly, with potentially reversible vision loss. Treatment with steroids and/or immunomodulatory agents (e.g., MMF, methotrexate) can lead to substantial improvements in visual function, including restoration of visual fields and resolution of CME, even in patients refractory to carbonic anhydrase inhibitors. The findings challenge the notion that these autoantibodies are merely secondary markers of degeneration. Recognizing and treating inflammation is crucial for optimizing outcomes in IRD patients, particularly to avoid confounding natural history studies and to ensure patients remain eligible for gene-specific therapies. The study also highlights the risk of post-cataract surgery inflammatory exacerbation and the importance of preoperative evaluation and treatment. Further prospective studies and clinical trials (e.g., intravitreal methotrexate for P23H RHO, NCT05392179) are warranted to establish optimal treatment protocols.

PICO

PPOPULATION

Patients referred for possible IRD who exhibited inflammatory signs and underwent autoantibody testing between 2016 and 2022 at the Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases

IINTERVENTION

Detection and characterization of anti-retinal and anti-optic nerve autoantibodies by Western blot and retinal immunohistochemistry; treatment (where applicable) with intravitreal and/or sub-Tenon steroid injections and/or immunomodulatory therapy (e.g., mycophenolate mofetil)

OOUTCOME

Presence and patterns of autoantibodies, correlation with clinical and imaging findings of inflammation (e.g., cystoid macular edema, optic nerve leakage on IVFA, RNFL thickening on OCT), and visual function changes (visual acuity, visual fields, ERG) following treatment

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10135873

The double-edged sword of inflammation in inherited retinal degenerations: Clinical and preclinical evidence for mechanistically and prognostically impactful but treatable complications

Frontiers in Cell and Developmental Biology

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Abstract We present retrospective data from our clinical research efforts of the past several years alongside a review of past and current clinical and preclinical data independently by several investigators supporting our clinical evidence for the importance of inflammation in inherited retinal degenerations (IRDs). We show how inflammation is a complicating factor in IRDs but, if recognized and managed, also a great opportunity to mitigate disease severity immediately, improve patient prognosis and quality of life, extend the treatment windows for gene-specific and agnostic therapeutic approaches, mitigate the impact of inflammatory complications on the accurate estimate of vision changes in IRD natural history studies, improve the chances of safer outcomes following cataract surgery, and potentially reduce the likelihood of inflammatory adverse events and augment the efficacy of viral vector-based treatment approaches to IRDs. Manuscript contribution to the field. Inflammation has been suspected to be at play in IRDs since the beginning of the 1900s and became a research focus through the early 1990s but was then largely abandoned in favor of genetic-focused research. Thanks to regained cognizance, better research tools, and a more holistic approach to IRDs, the recent reappraisal of the role of inflammation in IRDs has brought back to the surface its importance. A potential confounder in natural history studies and a limiting factor in clinical trials if not accounted for, inflammation can be managed and often offers an opportunity for immediately improved prognosis and outcomes for IRD patients. We present our retrospective clinical evidence for connections with a measurable secondary autoimmune component that can develop in IRDs and contribute to vision loss but is at least in part treatable. We also present ample lines of evidence from the literature corroborating our clinical observations at the preclinical level. Keywords: inherited retinal degeneration (IRD), inflammation, immune activation, treatment, prognosis

CITATION EXPORT

Kubra Sarici, Aanal Vyas, Alessandro Iannaccone. The double-edged sword of inflammation in inherited retinal degenerations: Clinical and preclinical evidence for mechanistically and prognostically impactful but treatable complications. Frontiers in Cell and Developmental Biology. (2023). https://doi.org/10.3389/fcell.2023.1177711

AUTHORS

3 · 1 CENTRES

Kubra Sarici, Aanal Vyas, Alessandro Iannaccone

1 Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases, Duke Eye Center, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, United States