Intravitreal TNF-α Inhibition in Extensive Macular Atrophy with Pseudodrusen-Like Appearance (EMAP): A Real-World Cohort Study

Intravitreal TNF-α Inhibition in Extensive Macular Atrophy with Pseudodrusen-Like Appearance (EMAP): A Real-World Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Intravitreal TNF-α Inhibition in Extensive Macular Atrophy with Pseudodrusen-Like Appearance (EMAP): A Real-World Cohort Study Rubens Camargo Siqueira, Tainara Souza Pinho, Thaís Queiroz Brito, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8888943/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To evaluate visual function, visual field preservation, and structural retinal stability in patients with Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) treated with intravitreal adalimumab, a tumor necrosis factor–alpha (TNF-α) inhibitor, in a real-world clinical setting. Methods This retrospective, observational cohort study included adult patients with a clinical diagnosis of EMAP who received three intravitreal injections of adalimumab (2 mg/0.05 mL) at baseline, Month 2, and Month 4. Best-corrected visual acuity (BCVA, logMAR) and automated perimetry parameters—Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI)—were analyzed using paired pre–post comparisons over a 6-month follow-up. Structural outcomes assessed ellipsoid zone (EZ) integrity and central macular thickness on optical coherence tomography (OCT). Full-field electroretinography (ERG) with 30-Hz flicker stimulation was used as a surrogate marker of macular cone function. Nonparametric statistics were applied due to non-normal data distribution. Results Nineteen patients (36 eyes) with paired BCVA data were analyzed. Mean BCVA remained stable from baseline (1.05 ± 0.48 logMAR) to follow-up (1.02 ± 0.42 logMAR), with a mean change of − 0.04 ± 0.25 logMAR (p = 0.28). Clinically, 19.4% of eyes showed a ≥ 0.2 logMAR gain, while 5.6% worsened, and 75% remained stable. Visual field analysis demonstrated no significant changes in MD, PSD, or FPDI, with a modest trend toward functional preservation. OCT analysis showed no significant progression of macular atrophy, EZ disruption, or changes in central macular thickness. ERG flicker responses remained stable in eyes with measurable signals. Conclusions In this real-world EMAP cohort, intravitreal adalimumab was associated with overall functional and structural stability over 6 months, without evidence of accelerated deterioration. These findings support the ocular safety and potential stabilizing role of TNF-α inhibition in EMAP and provide preliminary data to inform future controlled trials targeting inflammatory mechanisms in degenerative macular diseases. Ophthalmology Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) Intravitreal adalimumab TNF-α inhibition degenerative macular disease Retinal inflammation para-inflammation optical coherence tomography visual field preservation Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) is a rare and rapidly progressive degenerative macular phenotype, first described as a distinct clinical entity in 2009, characterized by early-onset bilateral macular atrophy, widespread pseudodrusen-like deposits, and accelerated loss of outer retinal structures, including photoreceptors and retinal pigment epithelium (RPE) [ 1 ]. Unlike typical dry age-related macular degeneration (AMD) or inherited retinal dystrophies such as retinitis pigmentosa, EMAP presents with earlier disease onset, faster progression, and simultaneous involvement of central and peripheral retinal function, resulting in substantial visual impairment at a relatively young age [ 1 – 4 ]. Subsequent natural history and imaging studies have demonstrated that EMAP is associated with rapid enlargement of macular atrophy, early disruption of the ellipsoid zone (EZ), progressive reduction in retinal sensitivity on microperimetry, and frequent development of severe visual disability [ 2 – 6 ]. Multimodal imaging, including spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF), and OCT angiography (OCTA), has revealed profound alterations of the outer retina, choriocapillaris impairment, and marked functional–structural dissociation, reinforcing the aggressive nature of this condition [ 6 – 10 ]. Although EMAP shares phenotypic similarities with advanced dry AMD, increasing evidence suggests that it represents a distinct degenerative spectrum, potentially overlapping with both age-related and inherited retinal disorders [ 4 , 5 , 8 ]. The absence of approved or evidence-based disease-modifying therapies for EMAP remains a major unmet clinical need, as current management is limited to supportive measures and monitoring for complications such as macular neovascularization [ 12 – 14 ]. From a pathophysiological standpoint, EMAP is increasingly recognized as a condition driven not only by structural degeneration but also by chronic para-inflammatory and immune-mediated mechanisms affecting the outer retina and RPE–choroid complex [ 4 , 7 , 8 ]. Histopathological and experimental data from related degenerative retinal diseases indicate a central role for microglial activation, complement dysregulation, oxidative stress, and blood–retinal barrier breakdown, processes that contribute to photoreceptor apoptosis and secondary cone degeneration [ 7 , 15 – 17 ]. Within this inflammatory milieu, tumor necrosis factor-alpha (TNF-α) has emerged as a key mediator of retinal neurotoxicity, amplifying inflammatory cascades and promoting neuronal cell death [ 15 , 18 ]. Preclinical studies in models of retinal degeneration have demonstrated that TNF-α inhibition can attenuate microglial overactivation, reduce cytokine-mediated retinal damage, and delay photoreceptor loss, providing a strong biological rationale for immunomodulatory strategies in degenerative retinal diseases [ 19 – 21 ]. In parallel, experimental and translational research has shown that blockade of TNF-α may exert neuroprotective effects on cones, which are particularly vulnerable in advanced stages of outer retinal degeneration [ 18 – 21 ]. Adalimumab, a fully human monoclonal antibody targeting TNF-α, has an established systemic safety profile and has been increasingly explored for local intraocular use in inflammatory and immune-mediated ocular conditions [ 22 – 26 ]. Several experimental and animal studies have demonstrated the absence of retinal toxicity following intravitreal adalimumab administration, even at supratherapeutic doses, with preserved retinal morphology and function on electrophysiological testing [ 27 – 30 ]. Furthermore, early clinical reports and pilot studies in noninfectious uveitis and intraocular inflammation support its ocular tolerability and local anti-inflammatory efficacy when administered intravitreally [ 24 – 26 ]. Despite this growing body of safety and mechanistic evidence, the potential role of intravitreal TNF-α inhibition in degenerative macular diseases, and specifically in EMAP, remains largely unexplored. To date, no clinical series have systematically evaluated functional, structural, and electrophysiological outcomes following intravitreal adalimumab in this aggressive macular phenotype. A recent systematic review and meta-analysis further reinforced the clinical and multimodal imaging spectrum of EMAP, consolidating diagnostic and phenotypic criteria across cohorts [ 29 ]. Therefore, the present study aimed to evaluate visual acuity, visual field preservation, and retinal structural stability in a real-world cohort of patients with EMAP treated with intravitreal adalimumab. By analyzing functional, imaging, and electrophysiological parameters over a 6-month follow-up period, this study seeks to provide foundational real-world evidence regarding the ocular safety and potential stabilizing effects of TNF-α inhibition in EMAP, thereby informing the design of future prospective and controlled clinical trials targeting inflammatory pathways in degenerative macular diseases. MATERIALS AND METHODS Study Design, Ethics, and Participants Study Design, Ethics, and Participants (versão final revisada) This study represents a retrospective analysis of a prospectively treated real-world cohort of patients with Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) who received intravitreal adalimumab under an ethics-approved clinical protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. Ethical approval was granted by the Brazilian National Research Ethics Committee (CONEP) under protocol CAAE 77066424.0.0000.0317. The protocol was registered at ClinicalTrials.gov (NCT07348588; Unique Protocol ID: ADARET). All participants had previously provided informed consent for intravitreal procedures and authorized the use of anonymized clinical data for research purposes. Although treatment was administered according to a predefined clinical protocol approved by the Ethics Committee, outcome analyses were performed retrospectively based on available clinical records. Eligible participants were adults aged 18 years or older with a clinical diagnosis of EMAP confirmed by multimodal retinal imaging, demonstrating widespread outer retinal and retinal pigment epithelium atrophy, pseudodrusen-like deposits, and peripheral retinal involvement. Inclusion criteria required the availability of paired best-corrected visual acuity (BCVA) measurements expressed in logMAR at baseline and after treatment. When available, paired automated visual field data, including Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI), were also analyzed. Eyes were excluded if there was evidence of concurrent retinal pathology capable of confounding functional outcomes, such as neovascular age-related macular degeneration, diabetic macular edema, or retinal vascular occlusion. Additional exclusion criteria included active or recent ocular infection or inflammation, significant media opacity precluding reliable imaging or functional testing, and intraocular surgery within three months prior to baseline, with the exception of uncomplicated phacoemulsification. When both eyes of a patient met eligibility criteria, each eye was included and analyzed independently. Intervention All included eyes received intravitreal adalimumab (Humira®, AbbVie Inc.) at a dose of 2 mg/0.05 mL, administered via pars plana injection using standard sterile technique. Procedures were performed under topical anesthesia with 5% povidone–iodine antisepsis, with an injection distance of 3.5 to 4.0 mm from the limbus, adjusted according to lens status. Following a protocol derived from prior prospective investigations, adalimumab was administered in a three-dose regimen, consisting of injections at baseline (Month 0), Month 2, and Month 4. Patients underwent safety evaluations 7–14 days after each injection, as well as at scheduled follow-up visits. No additional intraocular therapies were administered during the observation period. Clinical Assessments and Data Collection Best-corrected visual acuity was assessed using Snellen charts and converted to logMAR for statistical analysis. Measurements were obtained at baseline, prior to the first intravitreal injection, and at the post-treatment follow-up, defined as the first available visit after completion of the three-dose injection series. Only eyes with complete paired logMAR data were included in BCVA analyses. Automated static perimetry was performed using the iCare COMPASS system, employing either a 10 − 2 or 24 − 2 testing strategy, depending on disease severity and fixation stability. From these examinations, three functional indices were extracted: Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI). Visual field data were included only when both baseline and post-treatment measurements were available and considered reliable. Given the heterogeneity of real-world clinical records, a standardized data extraction protocol was applied. Values for right and left eyes were independently extracted from combined entries, and records labeled as “both eyes” were duplicated accordingly. A single transcription error identified during data verification was manually corrected. Non-numeric or non-measurable entries, such as “not performed” or “not measurable,” were excluded from quantitative analysis. Outcome Measures The primary outcome measure was the change in BCVA, expressed as ΔlogMAR (post-treatment minus baseline). Secondary outcomes included changes in automated perimetry parameters (ΔMD, ΔPSD, and ΔFPDI), as well as categorical analysis of visual acuity outcomes, including the proportion of eyes achieving a clinically meaningful improvement (≥ 0.2 logMAR gain) and the proportion demonstrating worsening (≥ 0.2 logMAR loss). Statistical Analysis All statistical analyses were performed using Python (NumPy, Pandas, and SciPy libraries). The distribution of paired differences was assessed using the Shapiro–Wilk test. When data deviated from normality, Wilcoxon signed-rank testswere applied for paired comparisons. Continuous variables are reported as mean ± standard deviation, median, and 95% confidence intervals, as appropriate. A two-sided p value < 0.05 was considered statistically significant. Given the exploratory real-world design and the rarity of EMAP, no formal a priori sample size calculation was performed. The sample size was determined by the number of eligible patients treated under the approved clinical protocol during the study period. A mixed-effects model accounting for intra-subject correlation was considered; however, given the exploratory nature of the study and limited sample size, eyes were analyzed independently. This represents a statistical limitation and results should be interpreted accordingly. RESULTS Visual Acuity Outcomes A total of 19 patients (36 eyes) with a clinical diagnosis of EMAP had complete paired best-corrected visual acuity (BCVA) data and were included in the visual acuity analysis. All included eyes received intravitreal adalimumab and were therefore analyzed as a single treatment cohort. At baseline, mean BCVA was 1.05 ± 0.48 logMAR, reflecting advanced functional impairment typical of this phenotype. At the post-treatment follow-up, mean BCVA was 1.02 ± 0.42 logMAR, indicating overall stability at the cohort level. The mean change in BCVA over the observation period (ΔlogMAR = post–pre) was − 0.04 ± 0.25, with a median change of 0.00, suggesting absence of systematic visual deterioration or improvement across the cohort. The 95% confidence interval ranged from − 0.12 to + 0.05 logMAR, encompassing both small improvements and small declines. Assessment of data distribution demonstrated non-normality of paired differences (Shapiro–Wilk p < 0.0001), and consequently, the Wilcoxon signed-rank test was applied, revealing no statistically significant change in BCVA over the 6-month follow-up period (p = 0.28). From a clinical perspective, heterogeneity of individual responses was observed. Seven of 36 eyes (19.4%) achieved a clinically meaningful improvement, defined as a gain of ≥ 0.2 logMAR, while two eyes (5.6%) experienced a clinically relevant worsening of ≥ 0.2 logMAR. The remaining 27 eyes (75.0%) remained functionally stable within ± 0.2 logMAR. Collectively, these findings indicate overall visual stability following intravitreal adalimumab in EMAP, with a notable subset of eyes demonstrating meaningful functional improvement. Visual Field Outcomes Automated visual field testing was available for 24 eyes for Mean Deviation (MD) and Pattern Standard Deviation (PSD), and for 22 eyes for the Field Preservation Deviation Index (FPDI). At baseline, the cohort exhibited substantial visual field impairment consistent with advanced disease stage. Mean Deviation showed a mild, non-significant improvement, changing from − 8.09 ± 3.58 dB at baseline to − 7.62 ± 3.57 dB at follow-up. The mean change (ΔMD) was + 0.47 ± 2.21 dB, with a 95% confidence interval ranging from − 0.46 to + 1.40 dB. This change did not reach statistical significance (Wilcoxon p = 0.20). Pattern Standard Deviation remained largely unchanged, increasing slightly from 9.29 ± 2.29 dB to 9.49 ± 2.06 dB (ΔPSD = + 0.20 ± 1.86 dB; p = 0.36), indicating stability of localized field irregularities. FPDI analysis revealed a modest trend toward functional preservation, with mean values increasing from 66.9% at baseline to 70.1% at follow-up. The mean change (ΔFPDI) was + 3.18 ± 8.38%, with a 95% confidence interval from − 0.53 to + 6.90%, although this trend did not achieve statistical significance (p = 0.15). Importantly, across all visual field metrics, no evidence of functional deterioration was observed at the cohort level, and small directional trends favored stabilization or mild improvement. Structural OCT and Electrophysiological Outcomes Structural evaluation using optical coherence tomography (OCT) demonstrated no significant changes in ellipsoid zone (EZ) integrity or central macular thickness over the 6-month follow-up period. Mean OCT-derived parameters remained stable from baseline to Month 6, with no signs of accelerated macular atrophy, outer retinal thinning, or treatment-related structural damage. Electrophysiological assessment was performed using full-field electroretinography (ERG) with 30-Hz flicker stimulation, serving as a surrogate marker of macular cone function. In eyes with measurable responses, both flicker amplitude and implicit time remained stable throughout the study period, with no statistically significant changesdetected between baseline and follow-up. Taken together, the OCT and ERG findings indicate structural and electrophysiological stability of the outer retina, supporting the ocular safety of intravitreal adalimumab and suggesting a stabilizing profile rather than progressive degeneration over the 6-month evaluation period. Safety Outcomes Throughout the 6-month follow-up period, no procedure-related serious ocular adverse events were observed in the treated eyes. Specifically, there were no clinical signs of intraocular inflammation, such as anterior chamber reaction, vitritis, or retinal vasculitis, and no cases of ocular infection, including endophthalmitis, were recorded. Intraocular pressure remained stable, with no clinically meaningful elevations attributable to treatment. Importantly, there was no evidence of treatment-related retinal toxicity, as supported by the absence of structural deterioration on OCT and the stability of electrophysiological parameters on full-field ERG. From a functional standpoint, no systematic reduction in best-corrected visual acuity or visual field sensitivity was detected at the cohort level. Collectively, these findings indicate that intravitreal adalimumab demonstrated a favorable ocular safety profile, without signs of inflammatory, infectious, or toxic effects, supporting the procedural safety and tolerability of this intervention in patients with EMAP over the observed period. Discussion Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) is a rare and aggressive degenerative retinal phenotype for which no disease-modifying therapy is currently available. Characterized by early-onset macular atrophy, widespread pseudodrusen-like deposits, and rapid loss of both central and peripheral visual function, EMAP represents a major unmet need in retinal therapeutics [ 1 – 5 ]. In this real-world cohort study, we evaluated the functional, structural, and electrophysiological outcomes of intravitreal adalimumab over a 6-month period and observed overall visual and anatomical stability, without evidence of treatment-related toxicity or accelerated degeneration. Given the typically progressive natural history of EMAP, short-term stabilization may represent a clinically meaningful signal. Functional Stability as a Clinically Meaningful Outcome in EMAP The natural history of EMAP is typically marked by relentless functional decline, with rapid enlargement of macular atrophy and progressive loss of retinal sensitivity documented in longitudinal cohorts [ 2 – 6 ]. Within this context, visual stability itself represents a clinically meaningful outcome. In our cohort, mean BCVA remained statistically unchanged over 6 months, with approximately three-quarters of eyes maintaining functional stability and nearly one-fifth achieving a clinically relevant gain of ≥ 0.2 logMAR. Only a small proportion of eyes experienced worsening, suggesting a favorable balance toward preservation rather than progression. Importantly, BCVA alone may underestimate disease progression in EMAP, as central acuity can remain relatively preserved until late stages despite ongoing photoreceptor loss [ 3 , 6 , 11 ]. Therefore, the inclusion of automated perimetry metrics—MD, PSD, and FPDI—provides a more sensitive assessment of functional integrity. The absence of significant deterioration in these parameters, together with a modest trend toward FPDI improvement, reinforces the interpretation of functional stabilization rather than mere statistical neutrality [ 3 , 11 , 12 ]. Structural and Electrophysiological Findings Support a Stabilizing Profile Structural OCT analysis demonstrated no significant progression of macular atrophy, ellipsoid zone (EZ) disruption, or central macular thinning during the observation period. In a disease characterized by early and rapid loss of outer retinal structures, EZ integrity has emerged as a robust biomarker of photoreceptor viability and visual prognosis [ 3 – 6 , 11 ]. The stability of EZ-related parameters in our cohort therefore supports a potential disease-stabilizing or neuroprotective signal, although causality cannot be inferred from this study design. Similarly, full-field ERG with 30-Hz flicker stimulation—used here as a surrogate marker of macular cone function—showed no significant changes in amplitude or implicit time. Although ERG is relatively insensitive to localized macular pathology, stability over time provides additional reassurance regarding retinal safety and the absence of generalized cone toxicity [ 19 , 27 , 28 ]. Biological Plausibility of TNF-α Inhibition in EMAP The rationale for TNF-α inhibition in EMAP is grounded in growing evidence that chronic para-inflammation plays a central role in outer retinal degeneration. EMAP shares mechanistic features with other inherited and degenerative retinal disorders, including microglial activation, complement dysregulation, oxidative stress, and blood–retinal barrier compromise [ 4 , 7 , 8 , 15 – 17 ]. TNF-α has been identified as a key mediator of secondary cone degeneration and photoreceptor apoptosis, acting through both direct neurotoxic signaling and amplification of inflammatory cascades [ 15 , 18 ]. Preclinical studies in animal models of retinal degeneration have consistently shown that TNF-α blockade can attenuate microglial overactivation, reduce cytokine-mediated retinal damage, and delay photoreceptor loss, supporting the biological plausibility of immunomodulatory strategies in degenerative retinal diseases [ 19 – 21 ]. In Brazilian cohorts, rheumatic fever and prolonged benzathine penicillin use have been identified as potential risk factors for EMAP, supporting a probable inflammatory component in its pathogenesis; however, the overall rarity of the disease even among patients with chronic rheumatic valvular inflammation suggests that systemic inflammation alone is insufficient and that additional susceptibility factors are required for disease manifestation [ 15 , 30 ].Although adalimumab was originally developed for systemic inflammatory disorders, intravitreal administration allows localized immunomodulation with minimal systemic exposure, a particularly attractive strategy in chronic retinal degeneration. Safety Profile and Comparison With Existing Literature A substantial body of experimental and translational literature has demonstrated the ocular safety of intravitreal adalimumab, even at supratherapeutic doses, with preserved retinal morphology and function in animal models [ 27 , 28 ]. Early clinical reports and pilot studies in noninfectious uveitis and breakthrough intraocular inflammation have also supported its local tolerability and anti-inflammatory efficacy [ 24 – 26 ]. In our cohort, no clinical signs of intraocular inflammation, infection, retinal toxicity, or functional deterioration were observed, corroborating these prior findings. Importantly, to date, no published clinical series have specifically evaluated TNF-α inhibition in EMAP, making direct comparisons challenging. Nevertheless, our findings parallel observations in other degenerative retinal diseases with inflammatory components, such as retinitis pigmentosa, in which immunomodulatory approaches have demonstrated signals of stabilization rather than dramatic functional recovery [ 19 , 27 , 28 ]. The concept of slowing disease progression, rather than reversing established atrophy, aligns with current therapeutic paradigms in neurodegenerative disorders. In this regard, the stability observed across multiple functional, structural, and electrophysiological endpoints in our cohort is encouraging and supports further investigation. Study Limitations Several limitations must be acknowledged. First, the retrospective and non-randomized design precludes definitive conclusions regarding efficacy and introduces potential selection and information bias. The absence of a matched untreated control group further limits causal inference regarding potential disease-modifying effects, as it is not possible to definitively distinguish treatment-related stabilization from natural interindividual variability or regression toward the mean. Second, the relatively short follow-up period of six months may not adequately capture the long-term trajectory of a chronic and progressive disease such as EMAP, which has been shown to evolve over years rather than months [ 4 – 6 ]. Although short-term stabilization is encouraging, longer observation periods are required to determine whether TNF-α inhibition can meaningfully alter the natural history of outer retinal atrophy. Third, eyes were analyzed as independent units, which may overestimate statistical power due to intra-subject correlation between fellow eyes. Although this approach is common in exploratory real-world studies, it represents a methodological limitation and results should be interpreted accordingly. Fourth, quantitative OCT-based measurements of atrophy area and systematic fundus autofluorescence analysis—recognized as sensitive biomarkers of EMAP progression—were not consistently available across all patients [ 6 , 11 – 13 ]. The absence of these standardized imaging metrics limits the ability to detect subtle structural progression. Nonetheless, given the rarity of EMAP and the absence of established disease-modifying therapies, real-world observational data represent an important first step toward hypothesis generation and rational trial design. Conclusions In summary, this real-world cohort study suggests that intravitreal TNF-α inhibition with adalimumab is associated with visual, structural, and electrophysiological stability in EMAP, without evidence of retinal toxicity over a 6-month period. While preliminary, these findings provide a compelling biological and clinical rationale for further investigation of immunomodulatory strategies in EMAP and related degenerative retinal diseases. Declarations Author Contributions Conceptualization: R.C.S.; Methodology: R.C.S., C.C.B.; Investigation: R.C.S., T.S.P., T.Q.B.; Data Curation: R.C.S.; Formal Analysis: R.C.S.; Writing—Original Draft Preparation: R.C.S.; Writing—Review & Editing: R.C.S., C.C.B.; Supervision: R.C.S.; Project Administration: R.C.S. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki and approved by the Brazilian National Research Ethics Committee (CONEP) under protocol CAAE 77066424.0.0000.0317. Informed Consent Statement Written informed consent was obtained from all subjects involved in the study. All participants authorized the use of anonymized clinical data for research purposes. Clinical Trial Registration The clinical protocol was registered at ClinicalTrials.gov (Identifier: NCT07348588; Unique Protocol ID: ADARET). Data Availability Statement The data presented in this study are available from the corresponding author upon reasonable request. The data are not publicly available due to ethical and privacy restrictions involving human participants. Conflicts of Interest The authors declare no conflict of interest. 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Ocul Immunol Inflamm . 2016;24(3):319–326. https://doi.org/10.3109/09273948.2014.990041 Velasco S, Gallego I, Olivares-González L, et al. Noninvasive ocular delivery of adalimumab-loaded nanostructured lipid carriers for targeted retinitis pigmentosa therapy. Biomed Pharmacother . 2025;185:117962. https://doi.org/10.1016/j.biopha.2025.117962 Olivares-González L, Velasco S, Millán JM, Rodrigo R. Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice. FASEB J . 2020;34(10):13839–13861. https://doi.org/10.1096/fj.202000044RR Martínez-Fernández de la Cámara C, Hernández-Pinto AM, Olivares-González L, et al. Adalimumab reduces photoreceptor cell death in a mouse model of retinal degeneration. Sci Rep . 2015;5:11764. https://doi.org/10.1038/srep11764 Arruda MP, Lima RV, Valle GSD, Zinher MT, de Menezes CE, Filho S, Bravo-Gonzalez A, Barbosa LIT, Nogueira HS, Anjos Filho VMD, Pereira SM, de Carvalho RAP, Lima LH. Clinical and Multimodal Imaging Findings in Extensive Macular Atrophy with Pseudodrusen (EMAP): A Systematic Review and Meta-Analysis. Am J Ophthalmol. 2026 Feb 9:S0002-9394(26)00068-1. doi: 10.1016/j.ajo.2026.02.006. Epub ahead of print. Cassavia Junior ASF, Bellanda V, Audi LO, Barbosa GCS, Caravelas RAM, Volpe GJ, Moreira HT, Schmidt A, Jorge R. Assessing the prevalence of extensive macular atrophy with pseudodrusen-like appearance in patients with rheumatic fever-associated valvular heart disease: a cross-sectional study. Int J Retina Vitreous. 2026 Feb 2;12(1):31. doi: 10.1186/s40942-026-00805-6. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8888943","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591793231,"identity":"dafdfe87-632e-4e56-a57e-835f0db2a01b","order_by":0,"name":"Rubens Camargo Siqueira","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYDACZhBhAGEfYGCwAVKMjQeI1MIM0pIG0tKAXwua5sMw63AD+XbmbRIfCu7Jm7f3HzxcUHPebm37YaAtNTbRuLQYHGYrk5xhUGw458xhhsMzjt1O3nYmEajlWFpuAy4tzDxm0jwGCYwzJJIZDvOw3U42OwDUwthwGKcW+Waglj8GCfYz5B8Dtfw7l2x2/iF+LUBlZtIMBgmJMySYGQ7zth2wM7tBwBagX4otewwSkmfwJBsc5u1LTjC7AbQlAY9f5PsPb7zx40+C7Qz2g48/83yzszc7n/7wwYcaG9wOg0c9FCSCVSbgVo6pxR6/4lEwCkbBKBiJAACM2V8JdgWudgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-4563-1570","institution":"Rubens Siqueira Research Center","correspondingAuthor":true,"prefix":"","firstName":"Rubens","middleName":"Camargo","lastName":"Siqueira","suffix":""},{"id":591796629,"identity":"9688bcf2-dad5-440c-8eb1-82d1922ce049","order_by":1,"name":"Tainara Souza Pinho","email":"","orcid":"","institution":"Medical School of São José do Rio Preto—FAMERP","correspondingAuthor":false,"prefix":"","firstName":"Tainara","middleName":"Souza","lastName":"Pinho","suffix":""},{"id":591796702,"identity":"a5ae6fa2-b280-49bc-bede-5c07e30bb768","order_by":2,"name":"Thaís Queiroz Brito","email":"","orcid":"","institution":"Rubens Siqueira Research Center","correspondingAuthor":false,"prefix":"","firstName":"Thaís","middleName":"Queiroz","lastName":"Brito","suffix":""},{"id":591796723,"identity":"5dcfb3f2-d58d-4225-b1f7-9a65510589ec","order_by":3,"name":"Cinara Cássia Brandão","email":"","orcid":"","institution":"Medical School of São José do Rio Preto—FAMERP","correspondingAuthor":false,"prefix":"","firstName":"Cinara","middleName":"Cássia","lastName":"Brandão","suffix":""}],"badges":[],"createdAt":"2026-02-16 01:10:09","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8888943/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8888943/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102909237,"identity":"80f15db4-153b-44df-bc86-7637d33b7f36","added_by":"auto","created_at":"2026-02-18 09:55:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":110902,"visible":true,"origin":"","legend":"\u003cp\u003eMean best-corrected visual acuity (BCVA) before and after intravitreal adalimumab in EMAP eyes.\u003cbr\u003e\nBar graph showing the mean BCVA (logMAR) of all EMAP eyes treated with intravitreal adalimumab (n = 36). Error bars represent the standard error of the mean (SEM). Visual acuity remained overall stable, with a slight trend toward improvement (mean ΔlogMAR = –0.04), although no statistically significant difference was observed (Wilcoxon signed-rank test, \u003cem\u003ep\u003c/em\u003e = 0.28).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8888943/v1/99fcdd23b9cdf70253a802a8.png"},{"id":102909599,"identity":"1a82ade9-06fb-4b56-9d86-5d39b836f32e","added_by":"auto","created_at":"2026-02-18 09:56:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":110902,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual eye trajectories of BCVA before and after intravitreal adalimumab in EMAP.\u003cbr\u003e\nSpaghetti plot illustrating BCVA changes for each eye (n = 36) from baseline to follow-up. The majority of eyes showed functional stability, while a subset exhibited meaningful improvement (gain ≥ 0.2 logMAR in 19.4% of eyes). Only 5.6% demonstrated ≥ 0.2 logMAR worsening, reflecting an overall pattern of visual preservation after treatment.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8888943/v1/3440f6f84b1d6b8840e0a0c8.png"},{"id":102909602,"identity":"f1e42087-609e-4af7-8b24-cd98c810a7fe","added_by":"auto","created_at":"2026-02-18 09:56:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":319459,"visible":true,"origin":"","legend":"\u003cp\u003ePre- and post-treatment visual field parameters in EMAP eyes following intravitreal adalimumab.\u003cbr\u003e\nBar graph displaying mean values of Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI) before and after intravitreal adalimumab. Error bars represent the standard error of the mean (SEM). MD showed a mild, non-significant improvement (+0.47 dB), PSD remained stable (+0.20 dB), and FPDI demonstrated a small trend toward functional preservation (+3.18%). Overall, visual field parameters remained stable, with no evidence of deterioration.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8888943/v1/215cbc933e605fa3f4bec14c.png"},{"id":102909792,"identity":"3be87fd6-d7e2-44ca-975c-f80d0645f950","added_by":"auto","created_at":"2026-02-18 09:56:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2467787,"visible":true,"origin":"","legend":"\u003cp\u003eBiological plausibility of TNF-α inhibition in Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP).\u003c/p\u003e\n\u003cp\u003eThe left panel illustrates the proposed pathogenic cascade underlying outer retinal degeneration in EMAP. Chronic para-inflammation, characterized by microglial activation, oxidative stress (ROS generation), complement dysregulation (e.g., C3a, C5a), and blood–retinal barrier (BRB) compromise, promotes sustained TNF-α signaling. Elevated TNF-αamplifies neurotoxic inflammatory cascades, leading to photoreceptor apoptosis and progressive outer retinal degeneration.\u003c/p\u003e\n\u003cp\u003eThe right panel depicts the therapeutic rationale for intravitreal TNF-αinhibition (e.g., adalimumab). TNF-α blockade is hypothesized to mitigate microglial overactivation, reduce cytokine-mediated retinal damage, attenuate oxidative stress and complement activation, and ultimately delay photoreceptor loss. Collectively, these mechanisms support the biological plausibility of immunomodulatory strategies aimed at preserving photoreceptor integrity in EMAP.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8888943/v1/9b9be045439f3c23ce6a0377.png"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eIntravitreal TNF-α Inhibition in Extensive Macular Atrophy with Pseudodrusen-Like Appearance (EMAP): A Real-World Cohort Study\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eExtensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) is a rare and rapidly progressive degenerative macular phenotype, first described as a distinct clinical entity in 2009, characterized by early-onset bilateral macular atrophy, widespread pseudodrusen-like deposits, and accelerated loss of outer retinal structures, including photoreceptors and retinal pigment epithelium (RPE) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Unlike typical dry age-related macular degeneration (AMD) or inherited retinal dystrophies such as retinitis pigmentosa, EMAP presents with earlier disease onset, faster progression, and simultaneous involvement of central and peripheral retinal function, resulting in substantial visual impairment at a relatively young age [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSubsequent natural history and imaging studies have demonstrated that EMAP is associated with rapid enlargement of macular atrophy, early disruption of the ellipsoid zone (EZ), progressive reduction in retinal sensitivity on microperimetry, and frequent development of severe visual disability [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Multimodal imaging, including spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF), and OCT angiography (OCTA), has revealed profound alterations of the outer retina, choriocapillaris impairment, and marked functional\u0026ndash;structural dissociation, reinforcing the aggressive nature of this condition [\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough EMAP shares phenotypic similarities with advanced dry AMD, increasing evidence suggests that it represents a distinct degenerative spectrum, potentially overlapping with both age-related and inherited retinal disorders [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The absence of approved or evidence-based disease-modifying therapies for EMAP remains a major unmet clinical need, as current management is limited to supportive measures and monitoring for complications such as macular neovascularization [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a pathophysiological standpoint, EMAP is increasingly recognized as a condition driven not only by structural degeneration but also by chronic para-inflammatory and immune-mediated mechanisms affecting the outer retina and RPE\u0026ndash;choroid complex [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Histopathological and experimental data from related degenerative retinal diseases indicate a central role for microglial activation, complement dysregulation, oxidative stress, and blood\u0026ndash;retinal barrier breakdown, processes that contribute to photoreceptor apoptosis and secondary cone degeneration [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Within this inflammatory milieu, tumor necrosis factor-alpha (TNF-α) has emerged as a key mediator of retinal neurotoxicity, amplifying inflammatory cascades and promoting neuronal cell death [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreclinical studies in models of retinal degeneration have demonstrated that TNF-α inhibition can attenuate microglial overactivation, reduce cytokine-mediated retinal damage, and delay photoreceptor loss, providing a strong biological rationale for immunomodulatory strategies in degenerative retinal diseases [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In parallel, experimental and translational research has shown that blockade of TNF-α may exert neuroprotective effects on cones, which are particularly vulnerable in advanced stages of outer retinal degeneration [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdalimumab, a fully human monoclonal antibody targeting TNF-α, has an established systemic safety profile and has been increasingly explored for local intraocular use in inflammatory and immune-mediated ocular conditions [\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Several experimental and animal studies have demonstrated the absence of retinal toxicity following intravitreal adalimumab administration, even at supratherapeutic doses, with preserved retinal morphology and function on electrophysiological testing [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Furthermore, early clinical reports and pilot studies in noninfectious uveitis and intraocular inflammation support its ocular tolerability and local anti-inflammatory efficacy when administered intravitreally [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite this growing body of safety and mechanistic evidence, the potential role of intravitreal TNF-α inhibition in degenerative macular diseases, and specifically in EMAP, remains largely unexplored. To date, no clinical series have systematically evaluated functional, structural, and electrophysiological outcomes following intravitreal adalimumab in this aggressive macular phenotype. A recent systematic review and meta-analysis further reinforced the clinical and multimodal imaging spectrum of EMAP, consolidating diagnostic and phenotypic criteria across cohorts [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, the present study aimed to evaluate visual acuity, visual field preservation, and retinal structural stability in a real-world cohort of patients with EMAP treated with intravitreal adalimumab. By analyzing functional, imaging, and electrophysiological parameters over a 6-month follow-up period, this study seeks to provide foundational real-world evidence regarding the ocular safety and potential stabilizing effects of TNF-α inhibition in EMAP, thereby informing the design of future prospective and controlled clinical trials targeting inflammatory pathways in degenerative macular diseases.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eStudy Design, Ethics, and Participants\u003c/p\u003e \u003cp\u003eStudy Design, Ethics, and Participants (vers\u0026atilde;o final revisada)\u003c/p\u003e \u003cp\u003e This study represents a retrospective analysis of a prospectively treated real-world cohort of patients with Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) who received intravitreal adalimumab under an ethics-approved clinical protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. Ethical approval was granted by the Brazilian National Research Ethics Committee (CONEP) under protocol CAAE 77066424.0.0000.0317. The protocol was registered at ClinicalTrials.gov (NCT07348588; Unique Protocol ID: ADARET). All participants had previously provided informed consent for intravitreal procedures and authorized the use of anonymized clinical data for research purposes. Although treatment was administered according to a predefined clinical protocol approved by the Ethics Committee, outcome analyses were performed retrospectively based on available clinical records.\u003c/p\u003e \u003cp\u003eEligible participants were adults aged 18 years or older with a clinical diagnosis of EMAP confirmed by multimodal retinal imaging, demonstrating widespread outer retinal and retinal pigment epithelium atrophy, pseudodrusen-like deposits, and peripheral retinal involvement.\u003c/p\u003e \u003cp\u003eInclusion criteria required the availability of paired best-corrected visual acuity (BCVA) measurements expressed in logMAR at baseline and after treatment. When available, paired automated visual field data, including Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI), were also analyzed.\u003c/p\u003e \u003cp\u003eEyes were excluded if there was evidence of concurrent retinal pathology capable of confounding functional outcomes, such as neovascular age-related macular degeneration, diabetic macular edema, or retinal vascular occlusion. Additional exclusion criteria included active or recent ocular infection or inflammation, significant media opacity precluding reliable imaging or functional testing, and intraocular surgery within three months prior to baseline, with the exception of uncomplicated phacoemulsification. When both eyes of a patient met eligibility criteria, each eye was included and analyzed independently.\u003c/p\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003cp\u003eAll included eyes received intravitreal adalimumab (Humira\u0026reg;, AbbVie Inc.) at a dose of 2 mg/0.05 mL, administered via pars plana injection using standard sterile technique. Procedures were performed under topical anesthesia with 5% povidone\u0026ndash;iodine antisepsis, with an injection distance of 3.5 to 4.0 mm from the limbus, adjusted according to lens status.\u003c/p\u003e \u003cp\u003eFollowing a protocol derived from prior prospective investigations, adalimumab was administered in a three-dose regimen, consisting of injections at baseline (Month 0), Month 2, and Month 4. Patients underwent safety evaluations 7\u0026ndash;14 days after each injection, as well as at scheduled follow-up visits. No additional intraocular therapies were administered during the observation period.\u003c/p\u003e \u003cp\u003eClinical Assessments and Data Collection\u003c/p\u003e \u003cp\u003eBest-corrected visual acuity was assessed using Snellen charts and converted to logMAR for statistical analysis. Measurements were obtained at baseline, prior to the first intravitreal injection, and at the post-treatment follow-up, defined as the first available visit after completion of the three-dose injection series. Only eyes with complete paired logMAR data were included in BCVA analyses.\u003c/p\u003e \u003cp\u003eAutomated static perimetry was performed using the iCare COMPASS system, employing either a 10\u0026thinsp;\u0026minus;\u0026thinsp;2 or 24\u0026thinsp;\u0026minus;\u0026thinsp;2 testing strategy, depending on disease severity and fixation stability. From these examinations, three functional indices were extracted: Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI). Visual field data were included only when both baseline and post-treatment measurements were available and considered reliable.\u003c/p\u003e \u003cp\u003eGiven the heterogeneity of real-world clinical records, a standardized data extraction protocol was applied. Values for right and left eyes were independently extracted from combined entries, and records labeled as \u0026ldquo;both eyes\u0026rdquo; were duplicated accordingly. A single transcription error identified during data verification was manually corrected. Non-numeric or non-measurable entries, such as \u0026ldquo;not performed\u0026rdquo; or \u0026ldquo;not measurable,\u0026rdquo; were excluded from quantitative analysis.\u003c/p\u003e \u003cp\u003eOutcome Measures\u003c/p\u003e \u003cp\u003eThe primary outcome measure was the change in BCVA, expressed as ΔlogMAR (post-treatment minus baseline).\u003c/p\u003e \u003cp\u003eSecondary outcomes included changes in automated perimetry parameters (ΔMD, ΔPSD, and ΔFPDI), as well as categorical analysis of visual acuity outcomes, including the proportion of eyes achieving a clinically meaningful improvement (\u0026ge;\u0026thinsp;0.2 logMAR gain) and the proportion demonstrating worsening (\u0026ge;\u0026thinsp;0.2 logMAR loss).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using Python (NumPy, Pandas, and SciPy libraries). The distribution of paired differences was assessed using the Shapiro\u0026ndash;Wilk test. When data deviated from normality, Wilcoxon signed-rank testswere applied for paired comparisons. Continuous variables are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, median, and 95% confidence intervals, as appropriate. A two-sided p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Given the exploratory real-world design and the rarity of EMAP, no formal a priori sample size calculation was performed. The sample size was determined by the number of eligible patients treated under the approved clinical protocol during the study period. A mixed-effects model accounting for intra-subject correlation was considered; however, given the exploratory nature of the study and limited sample size, eyes were analyzed independently. This represents a statistical limitation and results should be interpreted accordingly.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eVisual Acuity Outcomes\u003c/p\u003e \u003cp\u003eA total of 19 patients (36 eyes) with a clinical diagnosis of EMAP had complete paired best-corrected visual acuity (BCVA) data and were included in the visual acuity analysis. All included eyes received intravitreal adalimumab and were therefore analyzed as a single treatment cohort. At baseline, mean BCVA was 1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48 logMAR, reflecting advanced functional impairment typical of this phenotype. At the post-treatment follow-up, mean BCVA was 1.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42 logMAR, indicating overall stability at the cohort level.\u003c/p\u003e \u003cp\u003eThe mean change in BCVA over the observation period (ΔlogMAR\u0026thinsp;=\u0026thinsp;post\u0026ndash;pre) was \u0026minus;\u0026thinsp;0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25, with a median change of 0.00, suggesting absence of systematic visual deterioration or improvement across the cohort. The 95% confidence interval ranged from \u0026minus;\u0026thinsp;0.12 to +\u0026thinsp;0.05 logMAR, encompassing both small improvements and small declines. Assessment of data distribution demonstrated non-normality of paired differences (Shapiro\u0026ndash;Wilk p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and consequently, the Wilcoxon signed-rank test was applied, revealing no statistically significant change in BCVA over the 6-month follow-up period (p\u0026thinsp;=\u0026thinsp;0.28).\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, heterogeneity of individual responses was observed. Seven of 36 eyes (19.4%) achieved a clinically meaningful improvement, defined as a gain of \u0026ge;\u0026thinsp;0.2 logMAR, while two eyes (5.6%) experienced a clinically relevant worsening of \u0026ge;\u0026thinsp;0.2 logMAR. The remaining 27 eyes (75.0%) remained functionally stable within \u0026plusmn;\u0026thinsp;0.2 logMAR. Collectively, these findings indicate overall visual stability following intravitreal adalimumab in EMAP, with a notable subset of eyes demonstrating meaningful functional improvement.\u003c/p\u003e \u003cp\u003eVisual Field Outcomes\u003c/p\u003e \u003cp\u003eAutomated visual field testing was available for 24 eyes for Mean Deviation (MD) and Pattern Standard Deviation (PSD), and for 22 eyes for the Field Preservation Deviation Index (FPDI). At baseline, the cohort exhibited substantial visual field impairment consistent with advanced disease stage.\u003c/p\u003e \u003cp\u003eMean Deviation showed a mild, non-significant improvement, changing from \u0026minus;\u0026thinsp;8.09\u0026thinsp;\u0026plusmn;\u0026thinsp;3.58 dB at baseline to \u0026minus;\u0026thinsp;7.62\u0026thinsp;\u0026plusmn;\u0026thinsp;3.57 dB at follow-up. The mean change (ΔMD) was +\u0026thinsp;0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;2.21 dB, with a 95% confidence interval ranging from \u0026minus;\u0026thinsp;0.46 to +\u0026thinsp;1.40 dB. This change did not reach statistical significance (Wilcoxon p\u0026thinsp;=\u0026thinsp;0.20). Pattern Standard Deviation remained largely unchanged, increasing slightly from 9.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.29 dB to 9.49\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06 dB (ΔPSD\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.86 dB; p\u0026thinsp;=\u0026thinsp;0.36), indicating stability of localized field irregularities.\u003c/p\u003e \u003cp\u003eFPDI analysis revealed a modest trend toward functional preservation, with mean values increasing from 66.9% at baseline to 70.1% at follow-up. The mean change (ΔFPDI) was +\u0026thinsp;3.18\u0026thinsp;\u0026plusmn;\u0026thinsp;8.38%, with a 95% confidence interval from \u0026minus;\u0026thinsp;0.53 to +\u0026thinsp;6.90%, although this trend did not achieve statistical significance (p\u0026thinsp;=\u0026thinsp;0.15). Importantly, across all visual field metrics, no evidence of functional deterioration was observed at the cohort level, and small directional trends favored stabilization or mild improvement.\u003c/p\u003e \u003cp\u003eStructural OCT and Electrophysiological Outcomes\u003c/p\u003e \u003cp\u003eStructural evaluation using optical coherence tomography (OCT) demonstrated no significant changes in ellipsoid zone (EZ) integrity or central macular thickness over the 6-month follow-up period. Mean OCT-derived parameters remained stable from baseline to Month 6, with no signs of accelerated macular atrophy, outer retinal thinning, or treatment-related structural damage.\u003c/p\u003e \u003cp\u003eElectrophysiological assessment was performed using full-field electroretinography (ERG) with 30-Hz flicker stimulation, serving as a surrogate marker of macular cone function. In eyes with measurable responses, both flicker amplitude and implicit time remained stable throughout the study period, with no statistically significant changesdetected between baseline and follow-up.\u003c/p\u003e \u003cp\u003eTaken together, the OCT and ERG findings indicate structural and electrophysiological stability of the outer retina, supporting the ocular safety of intravitreal adalimumab and suggesting a stabilizing profile rather than progressive degeneration over the 6-month evaluation period.\u003c/p\u003e \u003cp\u003eSafety Outcomes\u003c/p\u003e \u003cp\u003eThroughout the 6-month follow-up period, no procedure-related serious ocular adverse events were observed in the treated eyes. Specifically, there were no clinical signs of intraocular inflammation, such as anterior chamber reaction, vitritis, or retinal vasculitis, and no cases of ocular infection, including endophthalmitis, were recorded. Intraocular pressure remained stable, with no clinically meaningful elevations attributable to treatment. Importantly, there was no evidence of treatment-related retinal toxicity, as supported by the absence of structural deterioration on OCT and the stability of electrophysiological parameters on full-field ERG. From a functional standpoint, no systematic reduction in best-corrected visual acuity or visual field sensitivity was detected at the cohort level. Collectively, these findings indicate that intravitreal adalimumab demonstrated a favorable ocular safety profile, without signs of inflammatory, infectious, or toxic effects, supporting the procedural safety and tolerability of this intervention in patients with EMAP over the observed period.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eExtensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) is a rare and aggressive degenerative retinal phenotype for which no disease-modifying therapy is currently available. Characterized by early-onset macular atrophy, widespread pseudodrusen-like deposits, and rapid loss of both central and peripheral visual function, EMAP represents a major unmet need in retinal therapeutics [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this real-world cohort study, we evaluated the functional, structural, and electrophysiological outcomes of intravitreal adalimumab over a 6-month period and observed overall visual and anatomical stability, without evidence of treatment-related toxicity or accelerated degeneration. Given the typically progressive natural history of EMAP, short-term stabilization may represent a clinically meaningful signal.\u003c/p\u003e \u003cp\u003eFunctional Stability as a Clinically Meaningful Outcome in EMAP\u003c/p\u003e \u003cp\u003eThe natural history of EMAP is typically marked by relentless functional decline, with rapid enlargement of macular atrophy and progressive loss of retinal sensitivity documented in longitudinal cohorts [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Within this context, visual stability itself represents a clinically meaningful outcome. In our cohort, mean BCVA remained statistically unchanged over 6 months, with approximately three-quarters of eyes maintaining functional stability and nearly one-fifth achieving a clinically relevant gain of \u0026ge;\u0026thinsp;0.2 logMAR. Only a small proportion of eyes experienced worsening, suggesting a favorable balance toward preservation rather than progression.\u003c/p\u003e \u003cp\u003eImportantly, BCVA alone may underestimate disease progression in EMAP, as central acuity can remain relatively preserved until late stages despite ongoing photoreceptor loss [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, the inclusion of automated perimetry metrics\u0026mdash;MD, PSD, and FPDI\u0026mdash;provides a more sensitive assessment of functional integrity. The absence of significant deterioration in these parameters, together with a modest trend toward FPDI improvement, reinforces the interpretation of functional stabilization rather than mere statistical neutrality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStructural and Electrophysiological Findings Support a Stabilizing Profile\u003c/p\u003e \u003cp\u003eStructural OCT analysis demonstrated no significant progression of macular atrophy, ellipsoid zone (EZ) disruption, or central macular thinning during the observation period. In a disease characterized by early and rapid loss of outer retinal structures, EZ integrity has emerged as a robust biomarker of photoreceptor viability and visual prognosis [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The stability of EZ-related parameters in our cohort therefore supports a potential disease-stabilizing or neuroprotective signal, although causality cannot be inferred from this study design.\u003c/p\u003e \u003cp\u003eSimilarly, full-field ERG with 30-Hz flicker stimulation\u0026mdash;used here as a surrogate marker of macular cone function\u0026mdash;showed no significant changes in amplitude or implicit time. Although ERG is relatively insensitive to localized macular pathology, stability over time provides additional reassurance regarding retinal safety and the absence of generalized cone toxicity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBiological Plausibility of TNF-α Inhibition in EMAP\u003c/p\u003e \u003cp\u003eThe rationale for TNF-α inhibition in EMAP is grounded in growing evidence that chronic para-inflammation plays a central role in outer retinal degeneration. EMAP shares mechanistic features with other inherited and degenerative retinal disorders, including microglial activation, complement dysregulation, oxidative stress, and blood\u0026ndash;retinal barrier compromise [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. TNF-α has been identified as a key mediator of secondary cone degeneration and photoreceptor apoptosis, acting through both direct neurotoxic signaling and amplification of inflammatory cascades [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreclinical studies in animal models of retinal degeneration have consistently shown that TNF-α blockade can attenuate microglial overactivation, reduce cytokine-mediated retinal damage, and delay photoreceptor loss, supporting the biological plausibility of immunomodulatory strategies in degenerative retinal diseases [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In Brazilian cohorts, rheumatic fever and prolonged benzathine penicillin use have been identified as potential risk factors for EMAP, supporting a probable inflammatory component in its pathogenesis; however, the overall rarity of the disease even among patients with chronic rheumatic valvular inflammation suggests that systemic inflammation alone is insufficient and that additional susceptibility factors are required for disease manifestation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].Although adalimumab was originally developed for systemic inflammatory disorders, intravitreal administration allows localized immunomodulation with minimal systemic exposure, a particularly attractive strategy in chronic retinal degeneration.\u003c/p\u003e \u003cp\u003eSafety Profile and Comparison With Existing Literature\u003c/p\u003e \u003cp\u003eA substantial body of experimental and translational literature has demonstrated the ocular safety of intravitreal adalimumab, even at supratherapeutic doses, with preserved retinal morphology and function in animal models [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Early clinical reports and pilot studies in noninfectious uveitis and breakthrough intraocular inflammation have also supported its local tolerability and anti-inflammatory efficacy [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our cohort, no clinical signs of intraocular inflammation, infection, retinal toxicity, or functional deterioration were observed, corroborating these prior findings. Importantly, to date, no published clinical series have specifically evaluated TNF-α inhibition in EMAP, making direct comparisons challenging. Nevertheless, our findings parallel observations in other degenerative retinal diseases with inflammatory components, such as retinitis pigmentosa, in which immunomodulatory approaches have demonstrated signals of stabilization rather than dramatic functional recovery [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe concept of slowing disease progression, rather than reversing established atrophy, aligns with current therapeutic paradigms in neurodegenerative disorders. In this regard, the stability observed across multiple functional, structural, and electrophysiological endpoints in our cohort is encouraging and supports further investigation.\u003c/p\u003e \u003cp\u003eStudy Limitations\u003c/p\u003e \u003cp\u003eSeveral limitations must be acknowledged. First, the retrospective and non-randomized design precludes definitive conclusions regarding efficacy and introduces potential selection and information bias. The absence of a matched untreated control group further limits causal inference regarding potential disease-modifying effects, as it is not possible to definitively distinguish treatment-related stabilization from natural interindividual variability or regression toward the mean.\u003c/p\u003e \u003cp\u003eSecond, the relatively short follow-up period of six months may not adequately capture the long-term trajectory of a chronic and progressive disease such as EMAP, which has been shown to evolve over years rather than months [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although short-term stabilization is encouraging, longer observation periods are required to determine whether TNF-α inhibition can meaningfully alter the natural history of outer retinal atrophy.\u003c/p\u003e \u003cp\u003eThird, eyes were analyzed as independent units, which may overestimate statistical power due to intra-subject correlation between fellow eyes. Although this approach is common in exploratory real-world studies, it represents a methodological limitation and results should be interpreted accordingly.\u003c/p\u003e \u003cp\u003eFourth, quantitative OCT-based measurements of atrophy area and systematic fundus autofluorescence analysis\u0026mdash;recognized as sensitive biomarkers of EMAP progression\u0026mdash;were not consistently available across all patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The absence of these standardized imaging metrics limits the ability to detect subtle structural progression.\u003c/p\u003e \u003cp\u003eNonetheless, given the rarity of EMAP and the absence of established disease-modifying therapies, real-world observational data represent an important first step toward hypothesis generation and rational trial design.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, this real-world cohort study suggests that intravitreal TNF-α inhibition with adalimumab is associated with visual, structural, and electrophysiological stability in EMAP, without evidence of retinal toxicity over a 6-month period. While preliminary, these findings provide a compelling biological and clinical rationale for further investigation of immunomodulatory strategies in EMAP and related degenerative retinal diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: R.C.S.; Methodology: R.C.S., C.C.B.; Investigation: R.C.S., T.S.P., T.Q.B.; Data Curation: R.C.S.; Formal Analysis: R.C.S.; Writing\u0026mdash;Original Draft Preparation: R.C.S.; Writing\u0026mdash;Review \u0026amp; Editing: R.C.S., C.C.B.; Supervision: R.C.S.; Project Administration: R.C.S. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Brazilian National Research Ethics Committee (CONEP) under protocol CAAE 77066424.0.0000.0317.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all subjects involved in the study. All participants authorized the use of anonymized clinical data for research purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical protocol was registered at ClinicalTrials.gov (Identifier: NCT07348588; Unique Protocol ID: ADARET).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study are available from the corresponding author upon reasonable request. The data are not publicly available due to ethical and privacy restrictions involving human participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eHamel CP, Defoort-Dhellemmes S, Bron A, et al. 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Rheumatic fever and long-term use of benzathine penicillin as possible risk factors for extensive macular atrophy with pseudodrusen in a Brazilian cohort. \u003cem\u003eInt J Retina Vitreous\u003c/em\u003e. 2024;10:75.\u0026nbsp;https://doi.org/10.1186/s40942-024-00592-y\u003c/li\u003e\n \u003cli\u003eSiqueira RC, Brand\u0026atilde;o CC. The role of cytokines in degenerative retinal diseases: a comprehensive review.\u0026nbsp;\u003cem\u003eBiomedicines\u003c/em\u003e. 2025;13(7):1724.\u0026nbsp;https://doi.org/10.3390/biomedicines13071724\u003c/li\u003e\n \u003cli\u003eYoshida N, Ikeda Y, Notomi S, et al. Interleukin-1\u0026beta; induces blood-retinal barrier breakdown via endothelial nitric oxide synthase activation.\u0026nbsp;\u003cem\u003eAm J Pathol\u003c/em\u003e. 2009;175(2):675\u0026ndash;684.\u0026nbsp;https://doi.org/10.2353/ajpath.2009.080924\u003c/li\u003e\n \u003cli\u003ePaula \u0026Aacute;C, \u0026Aacute;vila MP, Isaac DL, et al. Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells.\u0026nbsp;\u003cem\u003eArq Bras Oftalmol\u003c/em\u003e. 2015;78(2):89\u0026ndash;93.\u0026nbsp;https://doi.org/10.5935/0004-2749.20150024\u003c/li\u003e\n \u003cli\u003eManzano RP, Peyman GA, Carvounis PE, et al. Toxicity of high-dose intravitreal adalimumab in the rabbit.\u0026nbsp;\u003cem\u003eJ Ocul Pharmacol Ther\u003c/em\u003e. 2011;27(4):327\u0026ndash;331.\u0026nbsp;https://doi.org/10.1089/jop.2010.0174\u003c/li\u003e\n \u003cli\u003eMyers AC, Ghosh F, Andr\u0026eacute;asson S, Ponjavic V. Retinal function and morphology in the rabbit eye after intravitreal injection of adalimumab.\u0026nbsp;\u003cem\u003eCurr Eye Res\u003c/em\u003e. 2014;39(11):1106\u0026ndash;1116.\u0026nbsp;https://doi.org/10.3109/02713683.2014.898309\u003c/li\u003e\n \u003cli\u003eTsilimbaris M, Diakonis VF, Naoumidi I, et al. Evaluation of potential retinal toxicity of adalimumab (Humira).\u0026nbsp;\u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e. 2009;247(8):1119\u0026ndash;1125.\u0026nbsp;https://doi.org/10.1007/s00417-009-1065-y\u003c/li\u003e\n \u003cli\u003eHasan N, Chawla R, Shaikh N, et al. A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology.\u0026nbsp;\u003cem\u003eTher Adv Ophthalmol\u003c/em\u003e. 2022;14:25158414221097418.\u0026nbsp;https://doi.org/10.1177/25158414221097418\u003c/li\u003e\n \u003cli\u003eHassoun MM, Mahfoud ZR, Istambouli R, et al. Intravitreal versus subcutaneous adalimumab in active non-infectious uveitis: a randomized non-inferiority trial.\u0026nbsp;\u003cem\u003eOcul Immunol Inflamm\u003c/em\u003e. 2025.\u0026nbsp;https://doi.org/10.1080/09273948.2025.2526692\u003c/li\u003e\n \u003cli\u003eKheir WJ, Mehanna CJ, Abdul Fattah M, et al. Intravitreal adalimumab for the control of breakthrough intraocular inflammation.\u0026nbsp;\u003cem\u003eOcul Immunol Inflamm\u003c/em\u003e. 2018;26(8):1206\u0026ndash;1211.\u0026nbsp;https://doi.org/10.1080/09273948.2017.1335756\u003c/li\u003e\n \u003cli\u003eHamam RN, Barikian AW, Antonios RS, et al. Intravitreal adalimumab in active noninfectious uveitis: a pilot study.\u0026nbsp;\u003cem\u003eOcul Immunol Inflamm\u003c/em\u003e. 2016;24(3):319\u0026ndash;326.\u0026nbsp;https://doi.org/10.3109/09273948.2014.990041\u003c/li\u003e\n \u003cli\u003eVelasco S, Gallego I, Olivares-Gonz\u0026aacute;lez L, et al.\u0026nbsp;Noninvasive ocular delivery of adalimumab-loaded nanostructured lipid carriers for targeted retinitis pigmentosa therapy. \u003cem\u003eBiomed Pharmacother\u003c/em\u003e. 2025;185:117962.\u0026nbsp;https://doi.org/10.1016/j.biopha.2025.117962\u003c/li\u003e\n \u003cli\u003eOlivares-Gonz\u0026aacute;lez L, Velasco S, Mill\u0026aacute;n JM, Rodrigo R. Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice. \u003cem\u003eFASEB J\u003c/em\u003e. 2020;34(10):13839\u0026ndash;13861.\u0026nbsp;https://doi.org/10.1096/fj.202000044RR\u003c/li\u003e\n \u003cli\u003eMart\u0026iacute;nez-Fern\u0026aacute;ndez de la C\u0026aacute;mara C, Hern\u0026aacute;ndez-Pinto AM, Olivares-Gonz\u0026aacute;lez L, et al. Adalimumab reduces photoreceptor cell death in a mouse model of retinal degeneration. \u003cem\u003eSci Rep\u003c/em\u003e. 2015;5:11764. https://doi.org/10.1038/srep11764\u003c/li\u003e\n \u003cli\u003eArruda MP, Lima RV, Valle GSD, Zinher MT, de Menezes CE, Filho S, Bravo-Gonzalez A, Barbosa LIT, Nogueira HS, Anjos Filho VMD, Pereira SM, de Carvalho RAP, Lima LH. Clinical and Multimodal Imaging Findings in Extensive Macular Atrophy with Pseudodrusen (EMAP): A Systematic Review and Meta-Analysis. Am J Ophthalmol. 2026 Feb 9:S0002-9394(26)00068-1. doi: 10.1016/j.ajo.2026.02.006. Epub ahead of print.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCassavia Junior ASF, Bellanda V, Audi LO, Barbosa GCS, Caravelas RAM, Volpe GJ, Moreira HT, Schmidt A, Jorge R. Assessing the prevalence of extensive macular atrophy with pseudodrusen-like appearance in patients with rheumatic fever-associated valvular heart disease: a cross-sectional study. Int J Retina Vitreous. 2026 Feb 2;12(1):31. doi: 10.1186/s40942-026-00805-6.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP), Intravitreal adalimumab, TNF-α inhibition, degenerative macular disease, Retinal inflammation, para-inflammation, optical coherence tomography, visual field preservation","lastPublishedDoi":"10.21203/rs.3.rs-8888943/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8888943/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo evaluate visual function, visual field preservation, and structural retinal stability in patients with Extensive Macular Atrophy with Pseudodrusen-like Appearance (EMAP) treated with intravitreal adalimumab, a tumor necrosis factor\u0026ndash;alpha (TNF-α) inhibitor, in a real-world clinical setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective, observational cohort study included adult patients with a clinical diagnosis of EMAP who received three intravitreal injections of adalimumab (2 mg/0.05 mL) at baseline, Month 2, and Month 4. Best-corrected visual acuity (BCVA, logMAR) and automated perimetry parameters\u0026mdash;Mean Deviation (MD), Pattern Standard Deviation (PSD), and Field Preservation Deviation Index (FPDI)\u0026mdash;were analyzed using paired pre\u0026ndash;post comparisons over a 6-month follow-up. Structural outcomes assessed ellipsoid zone (EZ) integrity and central macular thickness on optical coherence tomography (OCT). Full-field electroretinography (ERG) with 30-Hz flicker stimulation was used as a surrogate marker of macular cone function. Nonparametric statistics were applied due to non-normal data distribution.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNineteen patients (36 eyes) with paired BCVA data were analyzed. Mean BCVA remained stable from baseline (1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48 logMAR) to follow-up (1.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42 logMAR), with a mean change of \u0026minus;\u0026thinsp;0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 logMAR (p\u0026thinsp;=\u0026thinsp;0.28). Clinically, 19.4% of eyes showed a\u0026thinsp;\u0026ge;\u0026thinsp;0.2 logMAR gain, while 5.6% worsened, and 75% remained stable. Visual field analysis demonstrated no significant changes in MD, PSD, or FPDI, with a modest trend toward functional preservation. OCT analysis showed no significant progression of macular atrophy, EZ disruption, or changes in central macular thickness. ERG flicker responses remained stable in eyes with measurable signals.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this real-world EMAP cohort, intravitreal adalimumab was associated with overall functional and structural stability over 6 months, without evidence of accelerated deterioration. These findings support the ocular safety and potential stabilizing role of TNF-α inhibition in EMAP and provide preliminary data to inform future controlled trials targeting inflammatory mechanisms in degenerative macular diseases.\u003c/p\u003e","manuscriptTitle":"Intravitreal TNF-α Inhibition in Extensive Macular Atrophy with Pseudodrusen-Like Appearance (EMAP): A Real-World Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-18 09:53:10","doi":"10.21203/rs.3.rs-8888943/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33fcf31e-c378-42e4-8a21-a2bb31367707","owner":[],"postedDate":"February 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62969145,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2026-02-18T09:53:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-18 09:53:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8888943","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8888943","identity":"rs-8888943","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}