RARE DISEASE
Intermediate uveitis
Intermediate uveitis
Intermediate uveitis
Synonyms: IU
Synonyms: IU
Synonyms: IU
Drug discovery
4
drugs
With orphan designations
Overview
Intermediate Uveitis (IU) is chronic inflammation predominantly affecting the vitreous and peripheral retina, defined by Standardization of Uveitis Nomenclature (SUN) criteria. While often idiopathic, adult cases may associate with multiple sclerosis or sarcoidosis. Pediatric IU (15-33% of childhood uveitis) frequently presents bilaterally with risks of macular edema (36%) and cataracts. Symptoms include floaters, blurred vision, and photophobia. Treatment combines corticosteroids with immunomodulators, though recurrence rates remain high, emphasizing early intervention [1][4][7][17].
Therapies
Stepwise approach: periocular/intravitreal corticosteroids → systemic steroids → immunomodulators (methotrexate, mycophenolate) → biologics (adalimumab) [2][3][8]
Surgical interventions (vitrectomy, cataract extraction) for complications [2][7]
61–85% achieve inflammation control with immunomodulators; biologics reduce relapse risk [3][8][18]
Categories: rare ophthalmic disorders
Research Papers
697 drug discovery papers about Intermediate uveitis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
697 drug discovery papers about Intermediate uveitis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-13 | Real-World Anatomical Outcomes of Suprachoroidal Triamcinolone Acetonide Injections in a Large Retinal Practice over a 4-Year Period.
To evaluate the clinical role, durability, anatomical response, and safety for suprachoroidal triamcinolone acetonide (SCTA) (Xipere) in routine clinical practice. Data were manually extracted from health records at a high-volume retina practice in Cleveland, Ohio. All patients with noninfectious inflammatory macular edema undergoing SCTA (≥1 billing code) between October 25, 2021, and July 17, 2025, were included. Patients with known systemic autoimmune or infectious associations were excluded. Unique eyes were defined by MRN + laterality, with "OU" entries split into OD/OS. Patient demographics, underlying diagnosis categorization, time between first and second injection (for eyes with ≥2 injections) were summarized. Pre- versus post-treatment central retinal thickness (CRT) and intraocular pressure (IOP) were compared via paired t-tests. A total of 177 patients (195 eyes) received 340 SCTA injections for macular edema associated with an underlying diagnosis of intermediate uveitis (10%), pseudophakic cystoid macular edema (31%), and posterior uveitis (59%). The time between first and second injection was approximately 5 months [SD ± 72.5; median 144 (min 35, max 427)]. From baseline to follow-up, mean CRT decreased by 103 µm [95% CI: (-122,-83.2), P < 0.001], while IOP increased minimally [mean difference 0.7 mmHg, 95% CI: (-0.02, 1.43), P = 0.057]; and was medically managed when elevated. In this real-world cohort, findings suggest that SCTA achieves robust anatomical improvement, a favorable IOP profile, and prolonged durability across patients with inflammation-related macular edema.
2026-06-02 | Granulomatous Panuveitis Associated with Body Piercing
To report a case of bilateral granulomatous panuveitis temporally associated with a body piercing and to highlight a potential immune-mediated mechanism analogous to tattoo-associated uveitis. This case included comprehensive clinical evaluation, multimodal ophthalmic imaging, and laboratory testing for infectious and systemic autoimmune disease. Treatments included corticosteroids and immunomodulatory therapy. A 16-year-old female with no past medical or ocular history and no history of tattoos developed progressive bilateral vision loss shortly after navel piercing placement. Her visual acuity was 20/200 in the right eye and hand motion in the left eye. Examination revealed granulomatous keratic precipitates, posterior synechiae, cataracts, vitritis, and disc edema, consistent with bilateral granulomatous panuveitis. Optical coherence tomography revealed diffuse intraretinal fluid, subretinal fluid, and bacillary detachment with a thick choroid. Fluorescein angiography showed disc leakage, macular leakage, and diffuse perivascular leakage. Intermediate-late-phase indocyanine green angiography demonstrated patchy hypofluorescent dark dots. Extensive infectious and systemic autoimmune work-up was negative. Her review of systems was negative. The patient achieved marked improvement and durable inflammation control with high doses of corticosteroids, methotrexate, and infliximab. We describe a case of bilateral granulomatous panuveitis temporally associated with a body piercing; however, causality cannot be established, and the proposed mechanism remains hypothesis-generating. Metal-specific delayed-type hypersensitivity or foreign body granulomatous inflammation, also implicated in tattoo-associated granulomatous uveitis, represents a plausible mechanism. Clinicians should inquire about recent tattoos or piercings when evaluating bilateral granulomatous uveitis of unclear origin, as early recognition and appropriate immunomodulatory therapy may prevent vision loss and morbidity.
2026-05-28 | Atypical COQ2-Related Retinopathy in Identical Twins with Nephropathy Mimicking Intermediate Uveitis.
To describe an atypical presentation of COQ2-related retinopathy in identical twins with nephropathy, mimicking intermediate uveitis with cystoid macular oedema (CMO). Retrospective case report. A 33-year-old man presented with bilateral vision worsening and suspected intermediate uveitis. Examination revealed vitreous cells, CMO, retinal microangiopathy, and severely abnormal electrooculography (EOG) with only borderline full-field electroretinography (ERG) changes. CMO worsened with topical corticosteroids but improved bilaterally after a single unilateral intravitreal bevacizumab injection, suggesting a systemic therapeutic effect. His identical twin exhibited very similar retinal and systemic findings. Whole-exome sequencing identified a homozygous likely pathogenic COQ2 variant (c.683A > G), confirming primary coenzyme Q10 (CoQ10) deficiency type 1. Both twins also had nephropathy consistent with focal segmental glomerulosclerosis (FSGS) but no neurological involvement. This report expands the phenotypic spectrum of COQ2-related retinopathy, characterized by retinal microangiopathy, CMO, and primary retinal pigment epithelium (RPE) dysfunction with preserved rod function, in contrast to the typical retinitis pigmentosa-like phenotype. Recognition of this presentation is critical, as early CoQ10 supplementation may stabilize disease progression and prevent systemic complications. Genetic testing should be considered in young patients with CMO resembling intermediate uveitis, particularly when associated with nephropathy.
2026-04-01 | Culprit and cure: Spontaneous closure of an inflammation-induced macular hole
A 59-year-old female presented with blurring of vision in OS for 1 year. She had been diagnosed to have intermediate uveitis due to sarcoidosis and received two doses of posterior subtenon injection of triamcinolone. On presentation to us, the best corrected visual acuity (BCVA) was 6/7.5 in OD and 2/60 in OS. Anterior segment examination revealed occasional cells and flare 1+ in and cells in anterior vitreous bilaterally. Fundus examination showed media haze due to vitritis [Fig. 1a and b], hyperemic disc, macular edema (CME) in OU with full thickness macular hole (MH) with a base diameter of 1023 µm, apex diameter 179 µm, and hole height 570 µm was observed in OS [Fig. 1b] by optical coherence tomography (OCT) [Fig. 1c]. Investigations showed alarmingly poor glycemic control. Intravitreal dexamethasone implant was administered in the left eye, and oral methotrexate (15 mg/week) was initiated. After 2 months, the visual acuity in OD improved to 6/6 and OS to 6/60 with improvement in inflammation in OU. Macular edema in OD resolved, while OS showed gradual anatomical improvement in OCT [Fig. 1d]. At 5 months, the MH had closed [Fig. 1e] and BCVA improved to 6/18. There was complete resolution of inflammation with immunosuppression, and oral methotrexate was continued. OCT at 10 months showing closure of hole with loss of ellipsoid zone layer and external limiting membrane [Fig. 1f].Figure 1: (a, b): Fundus photograph of right eye showing normal disc with cystic macula and left eye showing macular hole at presentation. (c): Left eye OCT at presentation showing full thickness macular hole with cystoid macular edema. (d): OCT at 2 months showing approximation of inner retinal layers with inner retinal cystic spaces. (e): OCT at 3 months showing inner layer closure with persistent outer layer defect. (f): OCT at 10 months showing closure of hole with loss of ellipsoid zone layer and external limiting membraneDiscussion The index case highlights that clinicians should exercise caution when managing MH in uveitis patients as those secondary to inflammatory CME may not always require surgical intervention.[1] The retinal thickening and increased volume caused by CME, which brings the edges of the MH closer together, result in closure due to primary intention. This proximity may facilitate the natural formation of a tissue “bridge” (often via glial or Müller cell proliferation) across the defect, allowing MH to close without surgical intervention.[2] According to a study by Wang et al., holes under 200 µm size have a substantial chance of MH closure with medical therapy. In the absence of anteroposterior traction, macular dehydration occurs and hole edges reoppose.[3,4] Authors’ contributions Dr. RK prepared the draft, Dr. SP collected the data, and images Dr. PDM was involved in patient management, provided additional inputs and finalized the manuscript. All the authors reviewed the final manuscript. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.
2026-04-01 | Longitudinal Follow-Up of Peripapillary Kyrieleis Plaques in a Case with Unilateral Intermediate Uveitis Related to Ocular Toxoplasmosis without a Focus of Retinochoroiditis.
To describe an atypical presentation of ocular toxoplasmosis, characterized by dense vitritis and circumferential peripapillary Kyrieleis plaques. Case report. A 49-year-old healthy man presented with right visual deterioration. He had previously received a short course oral corticosteroid treatment without systemic evaluation. On examination, dense vitritis and peripapillary, near-360 degrees Kyrieleis plaques without any focus of chorioretinitis were noted. Fluorescein angiography showed diffuse posterior pole masking from vitritis and mild late optic disc hyperfluorescence without peripheral vascular leakage. Infectious screening showed positive Toxoplasma gondii (IgG) and negative IgM. A diagnosis of ocular toxoplasmosis-related unilateral intermediate uveitis was established. Oral trimethoprim/sulfamethoxazole and azithromycin were initiated, resulting in improved visual acuity and reduced vitritis within three weeks. Five months later, new visual decline due to macular edema was treated with oral methylprednisolone and trimethoprim/sulfamethoxazole, leading to resolution. Over 10 months, Kyrieleis plaques decreased but did not fully disappear. Ocular toxoplasmosis can manifest atypically without a focus of retinochoroiditis. Kyrieleis plaques should prompt consideration of infectious causes before corticosteroid therapy.
antibodies
2026-01-07 | Systemic immunosuppressive therapy in idiopathic non-infectious uveitis and scleritis: disease remission, discontinuation, and relapse patterns.
Immunosuppressive therapy (IST) is indicated in idiopathic non-infectious uveitis and scleritis when local or topical treatments are insufficient, but long-term outcomes and predictors of relapse remain incompletely defined. We retrospectively reviewed clinical records of 110 patients with non-infectious uveitis or scleritis in the absence of systemic manifestation of disease who received IST. Time to remission, treatment duration, and relapse after IST withdrawal were analyzed by anatomic subtype. Predictors of remission and relapse were assessed using multivariable Cox and logistic regression models. Median follow-up was 84 months (IQR 48-135). Most patients achieved remission with first-line IST (79%), Methotrexate predominated in anterior (n = 27, 90%), intermediate (n = 13, 93%), and scleritis (n = 11, 85%), whereas cyclosporine was preferred in posterior (n = 20, 65%) and panuveitis (n = 12, 54%). Biological therapy (adalimumab) was used infrequently (n = 8, 7%). Median time to remission was 7 months (IQR 3.1-12.5), although posterior uveitis required significantly longer to remit (median 11 months; HR = 0.45 vs. AU, p = 0.005). Need for concomitant low-dose corticosteroids (≤10 mg/day) to achieve remission was associated with delayed remission (HR = 0.55, p = 0.006). IST was discontinued in 47% of patients, most commonly after ≥ 2 years due to disease control, while early discontinuation (< 2 years) was primarily due to adverse effects. Relapse occurred in 27% after withdrawal, typically within 10 months. Univariate analysis suggested differences by subtype, but only longer time to remission (p = 0.018) and shorter IST duration (p < 0.05) independently predicted relapse in multivariable models. IST effectively induced remission and reduced relapse rates in ocular-only non-infectious inflammation. Achieving early control (within six months) and maintaining IST for at least two years were associated with more durable remission. Posterior involvement and the need for concomitant low-dose oral corticosteroids reflected greater disease severity, whereas delayed remission and shorter IST duration independently predicted relapse.
2025-11-15 | Multiple sclerosis-associated uveitis successfully controlled with ofatumumab.
To report three cases of patients with multiple sclerosis (MS)-associated uveitis whose ocular inflammation responded well to ofatumumab. Case 1: A 26-year-old male with bilateral MS-associated occlusive retinal vasculitis presented with 1 + vitreous cell in both eyes and diffuse vascular leakage in both eyes on fluorescein angiography (FA). After treatment with ofatumumab for 19 months, there was significant improvement in vitreous cell and vascular leakage bilaterally. Case 2: A 41-year-old male with bilateral MS-associated intermediate uveitis presented with 2 + vitreous cell bilaterally. FA demonstrated bilateral vascular leakage with cystoid macular edema. After transitioning to ofatumumab from ocrelizumab and corticosteroid injections, exam remained quiet with resolved FA leakage bilaterally without further injections for 10 months. Case 3: A 51 year old female with MS initially presented with 2 + AC cell in the left eye and was started on mycophenolate mofetil with improvement but was unable to wean off topical corticosteroids. After switching to ofatumumab, she remained quiet on prednisolone acetate once daily in both eyes for nine months. While the benefits of ofatumumab have been well reported in MS, this is the first case report to describe the successful treatment of MS-associated uveitis with ofatumumab. Ofatumumab may prove to be an effective therapeutic option for these patients, with the additional benefit of self-administration. Further studies would be beneficial to identify the patients who would most benefit from this treatment.
2025-10-29 | Diagnostic and Therapeutic Strategies in Uveitis: A Clinical Approach
Uveitis refers to intraocular inflammation involving the uveal tract (iris, ciliary body, and choroid) and is a significant cause of ocular morbidity. It is responsible for a significant proportion of preventable vision loss worldwide. Uveitis can affect all age groups and often presents with eye pain, redness, photophobia, floaters, and blurred vision. It may be idiopathic or associated with systemic autoimmune diseases, infections, or trauma, and its clinical course ranges from acute to chronic. Anterior uveitis is the most common form across populations, whereas intermediate uveitis is relatively rare. Prompt diagnosis, thorough workup (including targeted laboratory tests and imaging), and appropriate therapy are critical to prevent vision-threatening complications. Management is centered on controlling inflammation with corticosteroids (topical, regional, or systemic) and immunomodulatory therapy (IMT) as needed, while addressing any underlying cause. A stepwise treatment approach is used, escalating therapy when necessary to achieve disease quiescence. Advances in ocular imaging—such as optical coherence tomography (OCT), anterior segment OCT, and fundus fluorescein angiography (FFA)—enhance diagnostic accuracy and monitoring. New therapeutic strategies, including biologic agents and intraocular drug delivery implants, have improved outcomes in refractory cases. This chapter provides an overview of uveitis classification, epidemiology, clinical evaluation, diagnostic algorithms, and evidence-based treatment strategies, illustrated by clinical cases and followed by a discussion of follow-up considerations and future directions in the management of uveitis.
2025-09-23 | Partial Response to Abatacept for Bilateral Asymmetrical Intermediate Uveitis in CTLA-4 Haploinsufficiency.
We report a case of bilateral asymmetrical intermediate uveitis in CTLA-4 haploinsufficiency and its response to abatacept. Retrospective case report and literature review. A 12-year-old male on sirolimus for control of autoimmune cytopenias in the context of CTLA-4 haploinsufficiency developed sudden onset reduced vision in his left eye after one year of treatment. He had bilateral anterior segment inflammation and disc oedema, with subretinal fibrosis in the left eye. Fluorescein angiography revealed the presence of non-occlusive retinal vasculitis with asymmetrical diffuse capillaritis in the left eye. Optical coherence tomography (OCT) showed cystoid macular oedema in the left eye. He was treated with topical and systemic corticosteroids, and commenced on abatacept infusions. After two years of treatment, there was complete remission of anterior segment inflammation, resolution of disc oedema and improvement of microvascular leakage on fluorescein angiography. To date, there have been two case reports identifying uveitis in patients with CTLA-4 haploinsufficiency, both of which responded well to abatacept. CTLA-4 haploinsufficiency may present with asymmetrical intermediate uveitis and abatacept has a potential role in its treatment. Our case demonstrates the response to treatment through sequential multimodal imaging, and has the longest reported follow-up to date.
2025-07-01 | Biologic Agents in Noninfectious Uveitis: A Comprehensive Review
Uveitis is a multifaceted condition characterized by inflammation affecting the anterior, intermediate, and posterior segments of the uveal tract, with etiologies ranging from inflammatory, infectious, to neoplastic origins. While various strategies exist to suppress the inflammatory response, the conventional approach of corticosteroid monotherapy, both locally and systemically, is increasingly deemed inadequate due to its significant side effects, prompting concerns. In recent years, biologic agents have emerged as promising alternatives for uveitis management. However, their widespread adoption is hindered by the considerable expense associated with these therapies, particularly impeding access in resource-limited settings. This review aims to provide a comprehensive analysis of available biologic treatment options for noninfectious uveitis, incorporating insights from clinical studies and recent advancements in pharmacology.
proteins
2025-11-13 | Repository Corticotropin Therapy for Refractory Noninfectious Inflammatory Ocular Diseases.
Objectives: To describe the outcomes of patients with refractory noninfectious ocular inflammatory diseases who underwent treatment with repository corticotropin injection (RCI). Methods: A retrospective cohort study was conducted. Patients who failed treatment with corticosteroids and were subsequently treated with RCI were included. Primary outcome measures were intraocular inflammatory activity, intraocular pressure (IOP), and the development of complications. Results: A total of 19 eyes from 10 patients were included. Most of the patients were women (70.0%) and the median age at presentation was 49.0 years (30.0-84.0 years). The ocular diagnoses were anterior/intermediate uveitis, intermediate/posterior uveitis, panuveitis, ocular cicatricial pemphigoid, and anterior scleritis. Seventeen (89.5%) eyes had active disease. The median duration of RCI treatment was 16.0 months (6.0-28.0 months). Nine (90.0%) patients, representing 17 (89.5%) eyes, achieved disease inactivity and remained quiescent at the last visit. No patient was on systemic corticosteroids at the last evaluation. The mean IOP was lower under RCI than corticosteroid at one month (16.0 mmHg ± 6.1 vs. 20.8 mmHg ± 9.5, p = 0.033) and four months (15.6 mmHg ± 2.9 vs. 17.8 mmHg ± 3.7, p = 0.046); however, the overall difference was not significant (16.2 mmHg ± 1.1 vs. 17.3 mmHg ± 1.8, p = 0.057). Incidence rates were the highest for posterior subcapsular cataracts (44.4% per eye-year). Relative risk analysis (RR) showed a 40.0% risk reduction for cystoid macular edema (RR = 0.60, p = 0.054). Conclusions: RCI may be an alternative treatment for refractory noninfectious ocular inflammatory diseases in patients who have failed treatment with corticosteroids.
2025-06-06 | Pharmacotherapy for non-infectious uveitis: spotlight on phase III clinical trials of locally injected or implanted therapeutics and systemic immunomodulatory drugs.
Non-infectious uveitis is an uncommon eye condition, but an important cause of substantial vision impairment and blindness around the world. An individualized treatment approach may include corticosteroids, conventional immunomodulatory medications, and biologic immunomodulatory agents, delivered locally to the eye or by systemic routes. In this narrative review, we describe pivotal phase III clinical trials that have provided the information guiding clinical practice in non-infectious uveitis today, focusing on studies of injected or surgically positioned local therapeutics, systemic immunomodulatory drugs, and the combination of both. We report on design, outcome measures, and key effectiveness and safety results of these trials. We also describe selected phase III clinical trials that are presently in progress, with results expected within the coming approximately 3 years. Finally, we summarize the state of the field and speculate on fruitful areas of research and development for new phase III clinical trials of drugs to treat non-infectious uveitis. The locally delivered therapeutics for non-infectious uveitis that have been studied in phase III clinical trials are largely corticosteroid-based. Trials have shown these locally placed corticosteroids to be effective, with complications that include elevated intraocular pressure and cataract. A minority of systemic immunomodulatory drugs used to treat non-infectious uveitis have been studied in phase III clinical trials. Key information obtained from those trials includes the following: similar effectiveness of methotrexate and mycophenolate mofetil for uveitis involving the posterior eye; usefulness of interferon-beta for intermediate uveitis; and potent anti-inflammatory activity of adalimumab in recalcitrant uveitis. Phase III clinical trials of immunomodulatory drugs with novel targets or routes of delivery can be anticipated in the foreseeable future. Interest in defining treatments for specific subsets of non-infectious uveitis through phase III clinical trials is also likely. For productive cross-referencing of clinical trial results, we recommend the use of core outcome measures.
2022-12-02 | Topical interferon therapy in uveitic macular edema.
To evaluate efficacy of topical interferon alfa-2b (IFN) in the treatment of uveitic macular edema (UME). This is a prospective, interventional case study of patients with UME. Injection IFN was reconstituted into eye drops and a four times/day (QID) application was prescribed. Central macular thickness (CMT) on optical coherence tomography (OCT) scan was evaluated. Improvement in CMT by ≥50 μm from the baseline was studied in eyes with presenting CMT ≥400 μm. Twenty eyes of 20 patients with UME were studied: anterior uveitis (n = 3), anterior + intermediate uveitis (n = 5), posterior uveitis (n = 3), retinal vasculitis (n = 3), and panuveitis (n = 6). Mean CMT at the presentation was 423.3 μm (range: 270-604 μm), which improved at 1 month (n = 16), 2 months (n = 10), and ≥3 months (n = 11) follow-up, to 415.3 μm (range: 247-579 μm) (P = 0.411), 364.4 μm (range: 258-566 μm) (P = 0.099), 344 μm (range: 258-484 μm) (P = 0.001), respectively. Twelve eyes of 12 patients had presenting CMT ≥400 μm. In these cases, decrease in CMT by ≥50 μm was seen in 4/10, 4/5, and 5/6 eyes at 1 and 2 months and ≥3 months follow-up. Mean follow-up was 4 months (range: 1-17 months). Complete resolution of UME was seen only in three eyes. No ocular or systemic side effects were observed. Topical IFN therapy in QID doses is safe but may have limited role in UME. Long-term therapy may improve its efficacy. Larger studies with dose modification, combination with other drugs, and with homogeneous uveitis population are recommended.
2021-09-29 | Efficacy and safety of immunomodulatory drugs in patients with non-infectious intermediate and posterior uveitis, panuveitis and macular edema: A systematic literature review.
Non-infectious non-anterior uveitis (NINA) is a sight-threatening condition that often requires immunomodulatory drugs (IMDs) for its management. To evaluate the published evidence regarding the use of IMDs in adult patients with NINA uveitis including intermediate (IU) and posterior uveitis (PU), panuveitis (PanU) and macular edema (ME). We performed a systematic literature review. Search strategies were designed for Medline, Embase, and Cochrane Libraries for articles up to 2019 to evaluate the efficacy and safety of the IMDs. A quality assessment was performed using the Jadad Scale. Nineteen randomized clinical trials were selected from the 1,103 articles retrieved. Characteristics of patients, treatment dosages and outcome measures were heterogeneous. The outcomes most frequently analyzed were visual acuity (VA), macular thickness and vitreous haze (VH). Different IMDs were used at their usual dosages. Methotrexate (MTX), micophenolate mofetil, cyclosporine A (CsA), tacrolimus, adalimumab and sarilumab were effective in NINA uveitis. Rituximab combined with MTX was effective in PU. Interferon-β was superior to MTX, albeit with more adverse events in IU with ME. CsA was similar to cyclophosphamide (Cyc) in Behçet uveitis. Tacrolimus was safer and similar to CsA. Cyc was effective in serpiginoid choroiditis, but when combined with azathioprine in PU, but did not improve VA. Secukinumab did not prevent NINA uveitis recurrences, although intravenously it showed a higher response rate than when used subcutaneously. Daclizumab did not show any benefits in Behçet NINA uveitis. Several IMDs and their combinations can be useful in treating NINA uveitis. The available studies were heterogeneous regarding patient characteristics and outcomes.
2021-06-14 | Regulated Tristetraprolin Overexpression Dampens the Development and Pathogenesis of Experimental Autoimmune Uveitis.
Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3'-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651-670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.
gene therapies
2025-04-18 | The clinical safety landscape for ocular AAV gene therapies: A systematic review and meta-analysis.
Adeno-associated virus (AAV) gene therapy is a promising approach for treating ocular monogenic or acquired diseases, though immunogenicity and safety remain critical considerations. We conducted a systematic review of 120 trials and 32 publications to assess immune responses across different delivery routes. Intravitreal administration was associated with higher rates of anterior uveitis (43.06% vs. 10.22%) and intermediate/posterior uveitis (40.36% vs. 6.18%) compared to subretinal delivery. Engineered AAV capsids, used exclusively in intravitreal studies, showed no significant difference in either type of uveitis incidence compared to natural serotypes. Prophylactic immunosuppression (PI) did not affect ocular or systemic immune responses in subretinal delivery, but significantly reduced systemic immune responses in intravitreal administration. These findings underscore the potential of PI to mitigate systemic immune responses in intravitreal AAV therapy. This review should help guide the choice of routes of administration and immunosuppression strategies, and highlights current trends in ocular AAV gene therapy.
2024-04-15 | AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?
Abstract Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.
2016-09-01 | Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines
The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNγ, TNFα and IL-17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNγ (150 ng/ml), TNFα (30 ng/ml) or IL-17 (100 ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IκBα expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNγ-induced SOCS1 mRNA increase and IFNγ-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNγ-induced decrease of IL-8 secretion and prevents IFNγ-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFα-induced IκBα degradation nor block TNFα-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17-induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNγ-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFα and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression.
2008-06-26 | Lentiviral-vector-mediated expression of murine IL-1 receptor antagonist or IL-10 reduces the severity of endotoxin-induced uveitis
Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.
small molecules
2026-06-13 | Real-World Anatomical Outcomes of Suprachoroidal Triamcinolone Acetonide Injections in a Large Retinal Practice over a 4-Year Period.
To evaluate the clinical role, durability, anatomical response, and safety for suprachoroidal triamcinolone acetonide (SCTA) (Xipere) in routine clinical practice. Data were manually extracted from health records at a high-volume retina practice in Cleveland, Ohio. All patients with noninfectious inflammatory macular edema undergoing SCTA (≥1 billing code) between October 25, 2021, and July 17, 2025, were included. Patients with known systemic autoimmune or infectious associations were excluded. Unique eyes were defined by MRN + laterality, with "OU" entries split into OD/OS. Patient demographics, underlying diagnosis categorization, time between first and second injection (for eyes with ≥2 injections) were summarized. Pre- versus post-treatment central retinal thickness (CRT) and intraocular pressure (IOP) were compared via paired t-tests. A total of 177 patients (195 eyes) received 340 SCTA injections for macular edema associated with an underlying diagnosis of intermediate uveitis (10%), pseudophakic cystoid macular edema (31%), and posterior uveitis (59%). The time between first and second injection was approximately 5 months [SD ± 72.5; median 144 (min 35, max 427)]. From baseline to follow-up, mean CRT decreased by 103 µm [95% CI: (-122,-83.2), P < 0.001], while IOP increased minimally [mean difference 0.7 mmHg, 95% CI: (-0.02, 1.43), P = 0.057]; and was medically managed when elevated. In this real-world cohort, findings suggest that SCTA achieves robust anatomical improvement, a favorable IOP profile, and prolonged durability across patients with inflammation-related macular edema.
2026-06-02 | Granulomatous Panuveitis Associated with Body Piercing
To report a case of bilateral granulomatous panuveitis temporally associated with a body piercing and to highlight a potential immune-mediated mechanism analogous to tattoo-associated uveitis. This case included comprehensive clinical evaluation, multimodal ophthalmic imaging, and laboratory testing for infectious and systemic autoimmune disease. Treatments included corticosteroids and immunomodulatory therapy. A 16-year-old female with no past medical or ocular history and no history of tattoos developed progressive bilateral vision loss shortly after navel piercing placement. Her visual acuity was 20/200 in the right eye and hand motion in the left eye. Examination revealed granulomatous keratic precipitates, posterior synechiae, cataracts, vitritis, and disc edema, consistent with bilateral granulomatous panuveitis. Optical coherence tomography revealed diffuse intraretinal fluid, subretinal fluid, and bacillary detachment with a thick choroid. Fluorescein angiography showed disc leakage, macular leakage, and diffuse perivascular leakage. Intermediate-late-phase indocyanine green angiography demonstrated patchy hypofluorescent dark dots. Extensive infectious and systemic autoimmune work-up was negative. Her review of systems was negative. The patient achieved marked improvement and durable inflammation control with high doses of corticosteroids, methotrexate, and infliximab. We describe a case of bilateral granulomatous panuveitis temporally associated with a body piercing; however, causality cannot be established, and the proposed mechanism remains hypothesis-generating. Metal-specific delayed-type hypersensitivity or foreign body granulomatous inflammation, also implicated in tattoo-associated granulomatous uveitis, represents a plausible mechanism. Clinicians should inquire about recent tattoos or piercings when evaluating bilateral granulomatous uveitis of unclear origin, as early recognition and appropriate immunomodulatory therapy may prevent vision loss and morbidity.
2026-05-28 | Atypical COQ2-Related Retinopathy in Identical Twins with Nephropathy Mimicking Intermediate Uveitis.
To describe an atypical presentation of COQ2-related retinopathy in identical twins with nephropathy, mimicking intermediate uveitis with cystoid macular oedema (CMO). Retrospective case report. A 33-year-old man presented with bilateral vision worsening and suspected intermediate uveitis. Examination revealed vitreous cells, CMO, retinal microangiopathy, and severely abnormal electrooculography (EOG) with only borderline full-field electroretinography (ERG) changes. CMO worsened with topical corticosteroids but improved bilaterally after a single unilateral intravitreal bevacizumab injection, suggesting a systemic therapeutic effect. His identical twin exhibited very similar retinal and systemic findings. Whole-exome sequencing identified a homozygous likely pathogenic COQ2 variant (c.683A > G), confirming primary coenzyme Q10 (CoQ10) deficiency type 1. Both twins also had nephropathy consistent with focal segmental glomerulosclerosis (FSGS) but no neurological involvement. This report expands the phenotypic spectrum of COQ2-related retinopathy, characterized by retinal microangiopathy, CMO, and primary retinal pigment epithelium (RPE) dysfunction with preserved rod function, in contrast to the typical retinitis pigmentosa-like phenotype. Recognition of this presentation is critical, as early CoQ10 supplementation may stabilize disease progression and prevent systemic complications. Genetic testing should be considered in young patients with CMO resembling intermediate uveitis, particularly when associated with nephropathy.
2026-04-01 | Culprit and cure: Spontaneous closure of an inflammation-induced macular hole
A 59-year-old female presented with blurring of vision in OS for 1 year. She had been diagnosed to have intermediate uveitis due to sarcoidosis and received two doses of posterior subtenon injection of triamcinolone. On presentation to us, the best corrected visual acuity (BCVA) was 6/7.5 in OD and 2/60 in OS. Anterior segment examination revealed occasional cells and flare 1+ in and cells in anterior vitreous bilaterally. Fundus examination showed media haze due to vitritis [Fig. 1a and b], hyperemic disc, macular edema (CME) in OU with full thickness macular hole (MH) with a base diameter of 1023 µm, apex diameter 179 µm, and hole height 570 µm was observed in OS [Fig. 1b] by optical coherence tomography (OCT) [Fig. 1c]. Investigations showed alarmingly poor glycemic control. Intravitreal dexamethasone implant was administered in the left eye, and oral methotrexate (15 mg/week) was initiated. After 2 months, the visual acuity in OD improved to 6/6 and OS to 6/60 with improvement in inflammation in OU. Macular edema in OD resolved, while OS showed gradual anatomical improvement in OCT [Fig. 1d]. At 5 months, the MH had closed [Fig. 1e] and BCVA improved to 6/18. There was complete resolution of inflammation with immunosuppression, and oral methotrexate was continued. OCT at 10 months showing closure of hole with loss of ellipsoid zone layer and external limiting membrane [Fig. 1f].Figure 1: (a, b): Fundus photograph of right eye showing normal disc with cystic macula and left eye showing macular hole at presentation. (c): Left eye OCT at presentation showing full thickness macular hole with cystoid macular edema. (d): OCT at 2 months showing approximation of inner retinal layers with inner retinal cystic spaces. (e): OCT at 3 months showing inner layer closure with persistent outer layer defect. (f): OCT at 10 months showing closure of hole with loss of ellipsoid zone layer and external limiting membraneDiscussion The index case highlights that clinicians should exercise caution when managing MH in uveitis patients as those secondary to inflammatory CME may not always require surgical intervention.[1] The retinal thickening and increased volume caused by CME, which brings the edges of the MH closer together, result in closure due to primary intention. This proximity may facilitate the natural formation of a tissue “bridge” (often via glial or Müller cell proliferation) across the defect, allowing MH to close without surgical intervention.[2] According to a study by Wang et al., holes under 200 µm size have a substantial chance of MH closure with medical therapy. In the absence of anteroposterior traction, macular dehydration occurs and hole edges reoppose.[3,4] Authors’ contributions Dr. RK prepared the draft, Dr. SP collected the data, and images Dr. PDM was involved in patient management, provided additional inputs and finalized the manuscript. All the authors reviewed the final manuscript. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.
2026-04-01 | Longitudinal Follow-Up of Peripapillary Kyrieleis Plaques in a Case with Unilateral Intermediate Uveitis Related to Ocular Toxoplasmosis without a Focus of Retinochoroiditis.
To describe an atypical presentation of ocular toxoplasmosis, characterized by dense vitritis and circumferential peripapillary Kyrieleis plaques. Case report. A 49-year-old healthy man presented with right visual deterioration. He had previously received a short course oral corticosteroid treatment without systemic evaluation. On examination, dense vitritis and peripapillary, near-360 degrees Kyrieleis plaques without any focus of chorioretinitis were noted. Fluorescein angiography showed diffuse posterior pole masking from vitritis and mild late optic disc hyperfluorescence without peripheral vascular leakage. Infectious screening showed positive Toxoplasma gondii (IgG) and negative IgM. A diagnosis of ocular toxoplasmosis-related unilateral intermediate uveitis was established. Oral trimethoprim/sulfamethoxazole and azithromycin were initiated, resulting in improved visual acuity and reduced vitritis within three weeks. Five months later, new visual decline due to macular edema was treated with oral methylprednisolone and trimethoprim/sulfamethoxazole, leading to resolution. Over 10 months, Kyrieleis plaques decreased but did not fully disappear. Ocular toxoplasmosis can manifest atypically without a focus of retinochoroiditis. Kyrieleis plaques should prompt consideration of infectious causes before corticosteroid therapy.
antibodies
2026-01-07 | Systemic immunosuppressive therapy in idiopathic non-infectious uveitis and scleritis: disease remission, discontinuation, and relapse patterns.
Immunosuppressive therapy (IST) is indicated in idiopathic non-infectious uveitis and scleritis when local or topical treatments are insufficient, but long-term outcomes and predictors of relapse remain incompletely defined. We retrospectively reviewed clinical records of 110 patients with non-infectious uveitis or scleritis in the absence of systemic manifestation of disease who received IST. Time to remission, treatment duration, and relapse after IST withdrawal were analyzed by anatomic subtype. Predictors of remission and relapse were assessed using multivariable Cox and logistic regression models. Median follow-up was 84 months (IQR 48-135). Most patients achieved remission with first-line IST (79%), Methotrexate predominated in anterior (n = 27, 90%), intermediate (n = 13, 93%), and scleritis (n = 11, 85%), whereas cyclosporine was preferred in posterior (n = 20, 65%) and panuveitis (n = 12, 54%). Biological therapy (adalimumab) was used infrequently (n = 8, 7%). Median time to remission was 7 months (IQR 3.1-12.5), although posterior uveitis required significantly longer to remit (median 11 months; HR = 0.45 vs. AU, p = 0.005). Need for concomitant low-dose corticosteroids (≤10 mg/day) to achieve remission was associated with delayed remission (HR = 0.55, p = 0.006). IST was discontinued in 47% of patients, most commonly after ≥ 2 years due to disease control, while early discontinuation (< 2 years) was primarily due to adverse effects. Relapse occurred in 27% after withdrawal, typically within 10 months. Univariate analysis suggested differences by subtype, but only longer time to remission (p = 0.018) and shorter IST duration (p < 0.05) independently predicted relapse in multivariable models. IST effectively induced remission and reduced relapse rates in ocular-only non-infectious inflammation. Achieving early control (within six months) and maintaining IST for at least two years were associated with more durable remission. Posterior involvement and the need for concomitant low-dose oral corticosteroids reflected greater disease severity, whereas delayed remission and shorter IST duration independently predicted relapse.
2025-11-15 | Multiple sclerosis-associated uveitis successfully controlled with ofatumumab.
To report three cases of patients with multiple sclerosis (MS)-associated uveitis whose ocular inflammation responded well to ofatumumab. Case 1: A 26-year-old male with bilateral MS-associated occlusive retinal vasculitis presented with 1 + vitreous cell in both eyes and diffuse vascular leakage in both eyes on fluorescein angiography (FA). After treatment with ofatumumab for 19 months, there was significant improvement in vitreous cell and vascular leakage bilaterally. Case 2: A 41-year-old male with bilateral MS-associated intermediate uveitis presented with 2 + vitreous cell bilaterally. FA demonstrated bilateral vascular leakage with cystoid macular edema. After transitioning to ofatumumab from ocrelizumab and corticosteroid injections, exam remained quiet with resolved FA leakage bilaterally without further injections for 10 months. Case 3: A 51 year old female with MS initially presented with 2 + AC cell in the left eye and was started on mycophenolate mofetil with improvement but was unable to wean off topical corticosteroids. After switching to ofatumumab, she remained quiet on prednisolone acetate once daily in both eyes for nine months. While the benefits of ofatumumab have been well reported in MS, this is the first case report to describe the successful treatment of MS-associated uveitis with ofatumumab. Ofatumumab may prove to be an effective therapeutic option for these patients, with the additional benefit of self-administration. Further studies would be beneficial to identify the patients who would most benefit from this treatment.
2025-10-29 | Diagnostic and Therapeutic Strategies in Uveitis: A Clinical Approach
Uveitis refers to intraocular inflammation involving the uveal tract (iris, ciliary body, and choroid) and is a significant cause of ocular morbidity. It is responsible for a significant proportion of preventable vision loss worldwide. Uveitis can affect all age groups and often presents with eye pain, redness, photophobia, floaters, and blurred vision. It may be idiopathic or associated with systemic autoimmune diseases, infections, or trauma, and its clinical course ranges from acute to chronic. Anterior uveitis is the most common form across populations, whereas intermediate uveitis is relatively rare. Prompt diagnosis, thorough workup (including targeted laboratory tests and imaging), and appropriate therapy are critical to prevent vision-threatening complications. Management is centered on controlling inflammation with corticosteroids (topical, regional, or systemic) and immunomodulatory therapy (IMT) as needed, while addressing any underlying cause. A stepwise treatment approach is used, escalating therapy when necessary to achieve disease quiescence. Advances in ocular imaging—such as optical coherence tomography (OCT), anterior segment OCT, and fundus fluorescein angiography (FFA)—enhance diagnostic accuracy and monitoring. New therapeutic strategies, including biologic agents and intraocular drug delivery implants, have improved outcomes in refractory cases. This chapter provides an overview of uveitis classification, epidemiology, clinical evaluation, diagnostic algorithms, and evidence-based treatment strategies, illustrated by clinical cases and followed by a discussion of follow-up considerations and future directions in the management of uveitis.
2025-09-23 | Partial Response to Abatacept for Bilateral Asymmetrical Intermediate Uveitis in CTLA-4 Haploinsufficiency.
We report a case of bilateral asymmetrical intermediate uveitis in CTLA-4 haploinsufficiency and its response to abatacept. Retrospective case report and literature review. A 12-year-old male on sirolimus for control of autoimmune cytopenias in the context of CTLA-4 haploinsufficiency developed sudden onset reduced vision in his left eye after one year of treatment. He had bilateral anterior segment inflammation and disc oedema, with subretinal fibrosis in the left eye. Fluorescein angiography revealed the presence of non-occlusive retinal vasculitis with asymmetrical diffuse capillaritis in the left eye. Optical coherence tomography (OCT) showed cystoid macular oedema in the left eye. He was treated with topical and systemic corticosteroids, and commenced on abatacept infusions. After two years of treatment, there was complete remission of anterior segment inflammation, resolution of disc oedema and improvement of microvascular leakage on fluorescein angiography. To date, there have been two case reports identifying uveitis in patients with CTLA-4 haploinsufficiency, both of which responded well to abatacept. CTLA-4 haploinsufficiency may present with asymmetrical intermediate uveitis and abatacept has a potential role in its treatment. Our case demonstrates the response to treatment through sequential multimodal imaging, and has the longest reported follow-up to date.
2025-07-01 | Biologic Agents in Noninfectious Uveitis: A Comprehensive Review
Uveitis is a multifaceted condition characterized by inflammation affecting the anterior, intermediate, and posterior segments of the uveal tract, with etiologies ranging from inflammatory, infectious, to neoplastic origins. While various strategies exist to suppress the inflammatory response, the conventional approach of corticosteroid monotherapy, both locally and systemically, is increasingly deemed inadequate due to its significant side effects, prompting concerns. In recent years, biologic agents have emerged as promising alternatives for uveitis management. However, their widespread adoption is hindered by the considerable expense associated with these therapies, particularly impeding access in resource-limited settings. This review aims to provide a comprehensive analysis of available biologic treatment options for noninfectious uveitis, incorporating insights from clinical studies and recent advancements in pharmacology.
proteins
2025-11-13 | Repository Corticotropin Therapy for Refractory Noninfectious Inflammatory Ocular Diseases.
Objectives: To describe the outcomes of patients with refractory noninfectious ocular inflammatory diseases who underwent treatment with repository corticotropin injection (RCI). Methods: A retrospective cohort study was conducted. Patients who failed treatment with corticosteroids and were subsequently treated with RCI were included. Primary outcome measures were intraocular inflammatory activity, intraocular pressure (IOP), and the development of complications. Results: A total of 19 eyes from 10 patients were included. Most of the patients were women (70.0%) and the median age at presentation was 49.0 years (30.0-84.0 years). The ocular diagnoses were anterior/intermediate uveitis, intermediate/posterior uveitis, panuveitis, ocular cicatricial pemphigoid, and anterior scleritis. Seventeen (89.5%) eyes had active disease. The median duration of RCI treatment was 16.0 months (6.0-28.0 months). Nine (90.0%) patients, representing 17 (89.5%) eyes, achieved disease inactivity and remained quiescent at the last visit. No patient was on systemic corticosteroids at the last evaluation. The mean IOP was lower under RCI than corticosteroid at one month (16.0 mmHg ± 6.1 vs. 20.8 mmHg ± 9.5, p = 0.033) and four months (15.6 mmHg ± 2.9 vs. 17.8 mmHg ± 3.7, p = 0.046); however, the overall difference was not significant (16.2 mmHg ± 1.1 vs. 17.3 mmHg ± 1.8, p = 0.057). Incidence rates were the highest for posterior subcapsular cataracts (44.4% per eye-year). Relative risk analysis (RR) showed a 40.0% risk reduction for cystoid macular edema (RR = 0.60, p = 0.054). Conclusions: RCI may be an alternative treatment for refractory noninfectious ocular inflammatory diseases in patients who have failed treatment with corticosteroids.
2025-06-06 | Pharmacotherapy for non-infectious uveitis: spotlight on phase III clinical trials of locally injected or implanted therapeutics and systemic immunomodulatory drugs.
Non-infectious uveitis is an uncommon eye condition, but an important cause of substantial vision impairment and blindness around the world. An individualized treatment approach may include corticosteroids, conventional immunomodulatory medications, and biologic immunomodulatory agents, delivered locally to the eye or by systemic routes. In this narrative review, we describe pivotal phase III clinical trials that have provided the information guiding clinical practice in non-infectious uveitis today, focusing on studies of injected or surgically positioned local therapeutics, systemic immunomodulatory drugs, and the combination of both. We report on design, outcome measures, and key effectiveness and safety results of these trials. We also describe selected phase III clinical trials that are presently in progress, with results expected within the coming approximately 3 years. Finally, we summarize the state of the field and speculate on fruitful areas of research and development for new phase III clinical trials of drugs to treat non-infectious uveitis. The locally delivered therapeutics for non-infectious uveitis that have been studied in phase III clinical trials are largely corticosteroid-based. Trials have shown these locally placed corticosteroids to be effective, with complications that include elevated intraocular pressure and cataract. A minority of systemic immunomodulatory drugs used to treat non-infectious uveitis have been studied in phase III clinical trials. Key information obtained from those trials includes the following: similar effectiveness of methotrexate and mycophenolate mofetil for uveitis involving the posterior eye; usefulness of interferon-beta for intermediate uveitis; and potent anti-inflammatory activity of adalimumab in recalcitrant uveitis. Phase III clinical trials of immunomodulatory drugs with novel targets or routes of delivery can be anticipated in the foreseeable future. Interest in defining treatments for specific subsets of non-infectious uveitis through phase III clinical trials is also likely. For productive cross-referencing of clinical trial results, we recommend the use of core outcome measures.
2022-12-02 | Topical interferon therapy in uveitic macular edema.
To evaluate efficacy of topical interferon alfa-2b (IFN) in the treatment of uveitic macular edema (UME). This is a prospective, interventional case study of patients with UME. Injection IFN was reconstituted into eye drops and a four times/day (QID) application was prescribed. Central macular thickness (CMT) on optical coherence tomography (OCT) scan was evaluated. Improvement in CMT by ≥50 μm from the baseline was studied in eyes with presenting CMT ≥400 μm. Twenty eyes of 20 patients with UME were studied: anterior uveitis (n = 3), anterior + intermediate uveitis (n = 5), posterior uveitis (n = 3), retinal vasculitis (n = 3), and panuveitis (n = 6). Mean CMT at the presentation was 423.3 μm (range: 270-604 μm), which improved at 1 month (n = 16), 2 months (n = 10), and ≥3 months (n = 11) follow-up, to 415.3 μm (range: 247-579 μm) (P = 0.411), 364.4 μm (range: 258-566 μm) (P = 0.099), 344 μm (range: 258-484 μm) (P = 0.001), respectively. Twelve eyes of 12 patients had presenting CMT ≥400 μm. In these cases, decrease in CMT by ≥50 μm was seen in 4/10, 4/5, and 5/6 eyes at 1 and 2 months and ≥3 months follow-up. Mean follow-up was 4 months (range: 1-17 months). Complete resolution of UME was seen only in three eyes. No ocular or systemic side effects were observed. Topical IFN therapy in QID doses is safe but may have limited role in UME. Long-term therapy may improve its efficacy. Larger studies with dose modification, combination with other drugs, and with homogeneous uveitis population are recommended.
2021-09-29 | Efficacy and safety of immunomodulatory drugs in patients with non-infectious intermediate and posterior uveitis, panuveitis and macular edema: A systematic literature review.
Non-infectious non-anterior uveitis (NINA) is a sight-threatening condition that often requires immunomodulatory drugs (IMDs) for its management. To evaluate the published evidence regarding the use of IMDs in adult patients with NINA uveitis including intermediate (IU) and posterior uveitis (PU), panuveitis (PanU) and macular edema (ME). We performed a systematic literature review. Search strategies were designed for Medline, Embase, and Cochrane Libraries for articles up to 2019 to evaluate the efficacy and safety of the IMDs. A quality assessment was performed using the Jadad Scale. Nineteen randomized clinical trials were selected from the 1,103 articles retrieved. Characteristics of patients, treatment dosages and outcome measures were heterogeneous. The outcomes most frequently analyzed were visual acuity (VA), macular thickness and vitreous haze (VH). Different IMDs were used at their usual dosages. Methotrexate (MTX), micophenolate mofetil, cyclosporine A (CsA), tacrolimus, adalimumab and sarilumab were effective in NINA uveitis. Rituximab combined with MTX was effective in PU. Interferon-β was superior to MTX, albeit with more adverse events in IU with ME. CsA was similar to cyclophosphamide (Cyc) in Behçet uveitis. Tacrolimus was safer and similar to CsA. Cyc was effective in serpiginoid choroiditis, but when combined with azathioprine in PU, but did not improve VA. Secukinumab did not prevent NINA uveitis recurrences, although intravenously it showed a higher response rate than when used subcutaneously. Daclizumab did not show any benefits in Behçet NINA uveitis. Several IMDs and their combinations can be useful in treating NINA uveitis. The available studies were heterogeneous regarding patient characteristics and outcomes.
2021-06-14 | Regulated Tristetraprolin Overexpression Dampens the Development and Pathogenesis of Experimental Autoimmune Uveitis.
Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3'-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651-670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.
gene therapies
2025-04-18 | The clinical safety landscape for ocular AAV gene therapies: A systematic review and meta-analysis.
Adeno-associated virus (AAV) gene therapy is a promising approach for treating ocular monogenic or acquired diseases, though immunogenicity and safety remain critical considerations. We conducted a systematic review of 120 trials and 32 publications to assess immune responses across different delivery routes. Intravitreal administration was associated with higher rates of anterior uveitis (43.06% vs. 10.22%) and intermediate/posterior uveitis (40.36% vs. 6.18%) compared to subretinal delivery. Engineered AAV capsids, used exclusively in intravitreal studies, showed no significant difference in either type of uveitis incidence compared to natural serotypes. Prophylactic immunosuppression (PI) did not affect ocular or systemic immune responses in subretinal delivery, but significantly reduced systemic immune responses in intravitreal administration. These findings underscore the potential of PI to mitigate systemic immune responses in intravitreal AAV therapy. This review should help guide the choice of routes of administration and immunosuppression strategies, and highlights current trends in ocular AAV gene therapy.
2024-04-15 | AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?
Abstract Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.
2016-09-01 | Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines
The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNγ, TNFα and IL-17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNγ (150 ng/ml), TNFα (30 ng/ml) or IL-17 (100 ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IκBα expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNγ-induced SOCS1 mRNA increase and IFNγ-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNγ-induced decrease of IL-8 secretion and prevents IFNγ-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFα-induced IκBα degradation nor block TNFα-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17-induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNγ-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFα and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression.
2008-06-26 | Lentiviral-vector-mediated expression of murine IL-1 receptor antagonist or IL-10 reduces the severity of endotoxin-induced uveitis
Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.
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Drug Discovery Landscape
4 orphan drug designations for Intermediate uveitis.
4 orphan drug designations for Intermediate uveitis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
tabirafusp alfa | proteins | FDA | 2025-03-04 | — | Kodiak Sciences Inc. |
vamikibart | antibodies | FDA | 2022-08-15 | — | Genentech, Inc |
Secukinumab [Cosantix] | antibodies | EMA | 2010-02-02 | — | Novartis Europharm Limited |
Voclosporin [Luveniq] | small molecules | EMA | 2007-09-14 | — | [INACTIVE] Lux Biosciences GmbH |
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