Retinal vasculitis is a potentially blinding condition characterized by inflammation of the retinal blood vessels. The annual incidence is estimated at 1 to 2 cases per 100,000 in the United States. Retinal vasculitis may be found in infectious, noninfectious, neoplastic uveitis and can be associated with systemic inflammatory disease.

In contrast to uveitis without retinal vasculitis, in which approximately 30% of cases may be idiopathic, uveitis associated with retinal vasculitis is less likely to be idiopathic. Furthermore, the underlying cause of retinal vasculitis is more likely to be systemic; however, ocular findings may be the first manifestation of systemic diseases that can be life-threatening and Over time, extraocular manifestations emerge, making the nature of the underlying systemic disease more apparent. Polyarteritis nodosa (PAN), Granulomatosis with polyangiitis (GPA), Systemic lupus erythematosus (SLE), Sarcoidosis, Multiple sclerosis (MS), Relapsing polychondritis (RPC), and Behçet’s disease, as well as infections such as Syphilis, Lyme disease, and Tuberculosis (TB), are examples of diseases that can behave in this way

Furthermore, the de novo onset of retinal vasculitis in a patient with a well-established systemic disease is clinically significant. For example, a patient with well-characterized Behçet’s disease, presenting with oral and genital ulcers, arthritis, and erythema nodosum, may be well controlled on twice-daily colchicine and low-dose prednisone. The development of retinal vasculitis, however, carries significant clinical implications. This indicates that the aforementioned therapeutic regimen will no longer be sufficient for this patient. The appearance of retinal vasculitis signals that the underlying nature of the patient’s Behçet’s disease has changed. Unless treatment is intensified, the patient is at risk of bilateral blindness within four years and has an approximately 30% risk of developing central nervous system vasculitis. Similar patterns are observed in patients with SLE, Relapsing polychondritis, GPA, and PAN. This concept is also relevant to idiopathic forms of retinal vasculitis.

The significance of retinal vasculitis, therefore, is considerable, both in terms of the likelihood of identifying an underlying systemic disease and as a marker of subclinical vasculitic involvement that may be life-threatening if not treated more aggressively.

Arash Maleki, MD; C. Stephen Foster, MD, FACS, FACR           April 2026

 

References

• Maleki A, Cao JH, Silpa-Archa S, Foster CS. VISUAL OUTCOME AND POOR PROGNOSTIC FACTORS IN ISOLATED IDIOPATHIC RETINAL VASCULITIS. Retina. 2016;36(10):1979-85.
• Maleki A, Ueberroth JA, Walsh M, Foster F, Chang PY, Anesi SD, Foster CS. Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases. Ocul Immunol Inflamm. 2021;29(7-8):1559-1563.
• Anesi SD, Chang PY, Maleki A, Manhapra A, Look-Why S, Asgari S, Walsh M, Drenen K, Foster CS. Effects of Subcutaneous Repository Corticotropin Gel Injection on Regulatory T Cell Population in Noninfectious Retinal Vasculitis. Ocul Immunol Inflamm. 2023;31(3):556-565.
• Maleki A, Garcia CM, Asgari S, Manhapra A, Foster CS. Response to the Second TNF-α Inhibitor (Adalimumab or Infliximab) after Failing the First One in Refractory Idiopathic Inflammatory Retinal Vascular Leakage. Ocul Immunol Inflamm. 2022;30(5):1099-1108.
• Anesi SD, Chang PY, Maleki A, Stephenson A, Montieth A, Filipowicz A, Syeda S, Asgari S, Walsh M, Metzinger JL, Foster CS. Treatment of Noninfectious Retinal Vasculitis Using Subcutaneous Repository Corticotropin Injection. J Ophthalmic Vis Res. 2021 Apr 29;16(2):219-233.

Immunomodulatory Therapy in Pediatric Uveitis,

A comprehensive review up to 2022

Arash Maleki, MD; C. Stephen Foster, MD, FACS, FACR

April 2026

The primary goal of treatment is to suppress active inflammation and decrease the risk of complications. If the cause of uveitis is an infection, appropriate therapy for that infection should be employed with or without anti-inflammatory therapy. Currently, despite recent and ongoing clinical trials, the non-infectious uveitis treatment is based on expert opinion and algorithms proposed by multi-disciplinary panels. A multi-disciplinary approach between pediatric rheumatologists and uveitis specialists is the key for successful treatment. Although corticosteroids are still the first line of treatment of acute uveitis, the major long-term goal of therapy is corticosteroid-free remission with corticosteroid-sparing immunomodulatory therapy. A step ladder approach is commonly employed in the treatment of pediatric patients with uveitis. This approach starts with the use of less potent medications and medications with better safety profiles and shifts to more potent medications with more potential side effects in patients with insufficient response. During corticosteroid free immunomodulatory therapy, high risk blood monitoring tests should be performed at regular intervals. These blood tests include complete blood count (CBC), liver function tests (LFTs), BUN and Cr. Patients on immunomodulatory therapy with conventional medications and biologic response modifying agents should avoid vaccination with live viruses. Almost all conventional immunomodulatory therapies are teratogenic and should be used with caution in child-bearing age.

 

Corticosteroids

The first line of treatment in pediatric anterior uveitis is often topical corticosteroids. Difluprednate 0.05% is the most potent topical corticosteroid; however, prednisolone acetate 1% is the most commonly used topical corticosteroid in uveitis. While topical corticosteroids are preferred over systemic corticosteroid therapy in most cases, systemic (oral and/or intravenous) and local (periocular and/or intraocular) injections can be considered for resistant, intermediate, posterior, and panuveitis. Slow-release intraocular implants such as dexamethasone intravitreal implant which can last up to 6 months and fluocinolone acetonide 0.19 mg which last for 3 years, are available for more severe cases. Cataract and glaucoma are the most common potential side effects of steroids, especially with intravitreal corticosteroids implants. Oral corticosteroids are used in inflammation recalcitrant to local therapy and in bilateral uveitis. Oral prednisone, at a dose of 1-2 mg/kg of body weight, is the most commonly prescribed oral corticosteroid. However, long-term systemic corticosteroid use should be avoided, especially in the pediatric age group, due to serious side effects including growth retardation, weight gain, hyperglycemia, infection, and osteoporosis. For other types of chronic uveitis in pediatric patients, the recommendations from the American College of Rheumatology/Arthritis Foundation for glucocorticoid use in JIA are employed. These include, 1) superiority of prednisolone acetate over difluprednate topical drops, 2) superiority of adding or increasing topical corticosteroids over systemic corticosteroids for controlling active inflammation, 3) superiority of topical corticosteroid over changing or escalating systemic therapy in patients with flare up on systemic therapy, 4) superiority of adding systemic therapy for patients who need 1-2 drops for controlling the inflammation, 5) in children and adolescents with JIA and CAU still requiring 1–2 drops/day of prednisolone acetate 1% (or equivalent) for at least 3 months and on systemic therapy for uveitis control, changing or escalating systemic therapy is conditionally recommended over maintaining current systemic therapy.¹⁴

 

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Naproxen and tolmentin have the longest history of successful treatment in pediatric uveitis. It has been shown that celecoxib and diflunisal may be useful in controlling anterior uveitis associated with seronegative spondyloarthropathies. These are not typically the drug of choice for different types of vasculitis.

 

Conventional Immunomodulatory Therapy

Since long-term use of corticosteroid can incur serious side effects, corticosteroid-sparing immunomodulatory therapy should be the next step in the stepladder approach for the treatment of pediatric uveitis. Conventional immunomodulatory therapies include methotrexate and less commonly used mycophenolate mofetil, azathioprine and cyclosporine. Methotrexate, mycophenolate mofetil, and azathioprine are all anti-metabolites while cyclosporine is considered a T-cell inhibitor. Anti-metabolites and T-cell inhibitors have additive effects on each other; however, anti-metabolites should not be used together preferably.

 

Methotrexate

Methotrexate is the most frequently used steroid-sparing agent in pediatric uveitis. Methotrexate is considered the first line of therapy in most cases of chronic non-infectious uveitis. The recommended starting dose is 10-15 mg/m² once a week orally or subcutaneously. Maximum dose is 30 mg/m²; however, doses higher than 15 mg/m² should be used subcutaneously due to the limited oral bioavailability of methotrexate. A meta-analysis demonstrated that methotrexate was effective in controlling pediatric non-infectious uveitis and the proportion of responding subjects was 0.73 in nine eligible studies. Common side effects of methotrexate include liver, renal and gastrointestinal toxicity. This medication should be used with folic acid supplements to help with normal cell proliferation and prevent side effects.

 

Mycophenolate Mofetil (MMF)

The optimal dose of MMF for uveitis is unknown; however, the therapy usually starts at a dose of 600 mg/m² twice a day and the max dose is 3 g/day in two divided doses. There are two reports of MMF therapy in pediatric patients. Although MMF is helpful in the treatment of non-infectious uveitis, it is less effective for arthritis in comparison with other agents. Leukopenia, gastrointestinal discomfort, and hair loss are major side effects.

 

Azathioprine

Azathioprine can be moderately effective in the pediatric population; however, it is less commonly used due to the increased risk of gastrointestinal side effects in comparison to other anti-metabolites. There are few case series which report the experience with azathioprine in JIA associated uveitis. An observational multi-center study showed that azathioprine may be helpful as a systemic monotherapy or in combination with other immunosuppressive agents in JIA associated uveitis. The safe and well-tolerated dose in children is 3 mg/kg in a single dose or divided dose.

 

Cyclosporine

It is important to note that cyclosporine is minimally effective as monotherapy; however, the efficacy of cyclosporine increases when it is combined with other immunomodulatory agents. Pediatric dosage of cyclosporine is 2.5 to 5.0 mg/kg/day in divided doses to prevent drug toxicity. Nephrotoxicity, hypertension, hepatotoxicity, hypercholesterolemia, and hirsutism are potential side effects. The dosage of cyclosporine is adjusted based on the medication level. Cyclosporine is infrequently employed in the treatment of uveitis in children.

 

Biologic Response modifiers

Biologic response modifiers are the next step of the stepladder approach after conventional immunomodulatory agents. These agents block target molecules in the immune system that play a role in the ocular inflammatory process. Therapeutic options include anti-tumor necrosis factor alpha (TNF-α), anti-interleukin 1 (IL-1), anti-B-cell, and anti-T-cell inhibitors. Viral hepatitis and tuberculosis should be ruled out before starting these agents. Out of all the biologic response modifier agents, anti-TNF-α agents have been studied most frequently.

 

Tumor Necrosis Factor Alpha Inhibitors (TNF-α inhibitors)

 

Infliximab

Infliximab is a chimeric (human-murine) monoclonal antibody that binds and inhibits circulating and membrane bound TNF-α. The efficacy and safety of infliximab have been studied in retrospective and prospective studies. Infliximab is administrated parenterally with a loading dose of 3-5 mg/kg at 0-2-6 weeks, followed by a maintenance dose of 3-10 mg/kg every 4 weeks. Low dose methotrexate is recommended to prevent antibody formation against the murine part of infliximab molecule. In refractory non-infectious uveitis, a higher dose of 20 mg/kg has been used successfully. Major side effects include susceptibility to infections, reactivation of tuberculosis and histoplasmosis, malignancy, and the development of lupus-like syndrome. Mild to moderate infusion reactions can be seen in 17% of patients.

 

Adalimumab

Adalimumab, a fully humanized monoclonal antibody, is the only biologic response modifier agent that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-infectious uveitis. Several studies have supported the efficacy of adalimumab in the treatment of pediatric uveitis. Antibody development against adalimumab has been reported in previous studies (13%). This is a favorite medication for ocular immunologists in the treatment of pediatric uveitis. Adalimumab is administered subcutaneously at a dose of 24 mg/m² up to maximum dose of 40 mg every 2 weeks; however, this interval can be shortened to weekly when the response is inadequate. It was demonstrated in a multicenter, double blind, randomized, placebo-controlled trial (SYCAMORE Trial) that adalimumab therapy-controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis on a stable dose of methotrexate.

Adalimumab was also shown to be effective in cases of early onset, chronic anterior uveitis with inadequate response to topical therapy and methotrexate.

A meta-analysis performed by Maccora et al. showed the efficacy of adalimumab and infliximab in the treatment of chronic childhood uveitis. However, the results from adalimumab use were superior to those associated with infliximab use in this clinical setting.

The side effect profile of adalimumab is similar to that of infliximab. The high efficacy in pediatric uveitis and ease of administration subcutaneously at home make it a good choice for both the patient and the family.

 

Abatacept, a T-cell inhibitor biologic agent

Abatacept is a soluble fusion protein which binds to CD80/CD86 on antigen presenting cells and prevents T-cell activation. A recent study described abatacept efficacy in 3 children with idiopathic uveitis. In a study by Tappenier and colleagues, 48% of patients on abatacept failed treatment and it was concluded that abatacept was not a successful treatment in pediatric uveitis. Dosing is 10 mg/kg at 0 and 15 days followed by monthly infusion. Alternatively, abatacept can also be employed as a subcutaneous injection at a dose of 125 mg weekly. Side effects include infection susceptibility, gastrointestinal symptoms, and low risk of malignancy. The efficacy of abatacept in pediatric uveitis is inconclusive.

 

Tocilizumab, an interleukin-6 (IL-6) inhibitor

Tocilizumab is a humanized recombinant anti-IL-6 receptor antibody which can inhibit T-cell activation, immunoglobulin secretion, and angiogenesis. We recently studied tocilizumab on 8 patients (14 eyes) with refractory JIA associated uveitis. The average duration of follow-up period after starting treatment was 28.6 ± 24.6 months (9-70). Intravenous tocilizumab infusions induced and maintained remission in 5 patients (8 eyes). Vasculitis was resolved within 8 months in all but one patient. We found that intravenous tocilizumab infusion can be an effective and safe method of treatment to induce and maintain remission in resistant JIA associated uveitis. Ramanan et al. studied tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis associated uveitis (APTITUDE trial). The aim of this phase two trial was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors; however, they did not meet the primary endpoint of their phase 2 trial to support a phase 3 trial of tocilizumab in patients with JIA-associated uveitis. Currently, there are two ongoing trials to study the efficacy of tocilizumab in noninfectious intermediate, posterior and panuveitis: (STOP-Uveitis) and JIA-associated uveitis (JIA-U). (www.clinicaltrials.gov) Tocilizumab has been proposed to be a promising agent for the treatment of pediatric uveitis; however, more studies are required for the ideal dose and interval. The current dose of medication is 165 mg/week through subcutaneous injections or 8 mg/kg of weight through monthly infusions. Monthly infusions of tocilizumab have been found to be more effective than weekly injections.

 

Rituximab, a B-cell inhibitor biologic agent

Rituximab is a chimeric antibody that targets the B-cell marker CD20 and subsequently induces B-cell apoptosis. Other mechanisms of action include receptor signaling, calcium flux, complement activation or attraction of antibody-dependent effector cells. Miserocchi and colleagues studied a cohort of 8 patients (15 eyes) with severe refractory JIA uveitis treated with rituximab. The mean number of infusions was 8.75 during mean 47.5 months follow-up (almost one infusion every 5 months). Uveitis was inactive in all patients at the last follow-up visit, and improvement was noted 4 months after the first infusion.

Rituximab is traditionally infused at a dose of 17 mg/kg per infusion which would result in a total dose of 70 mg/kg (4 weekly infusions). The long-lasting effect (6-9 months) of rituximab make it an attractive biologic agent. Rituximab in pediatrics is traditionally given slowly, administered at an initial rate of 0.5 mg/kg/hr for the first hour, and is gradually increased by 0.5 mg/kg/hr every 30 minutes based on the patient’s response (maximum rate of 50 mg/hr).

Side effects include infusion reaction, late neutropenia, hypogammaglobulinemia, heart failure, and rarely lethal progressive multifocal neuroencephalopathy (PMN). IgG monitoring may be useful for patients receiving rituximab since persistent hypogammaglobulinemia that required IgG replacement was noted in 4.2% of patients.

 

Emerging Biologics

Janus Kinase (JAK) inhibitors have been recently employed in the treatment of patients with uveitis and scleritis in adults. There is an ongoing open-label, active-controlled, safety, and efficacy study of oral baricitinib in patients from 2-18 years old with active JIA-associated uveitis or chronic anterior ANA-positive uveitis.

 

The recommendation of the American College of Rheumatology/Arthritis Foundation for immunomodulatory therapy in JIA which are mostly applied to other types of chronic uveitis in pediatric group include, 1) subcutaneous methotrexate is superior over oral methotrexate for starting treatment, 2) for a sight-threatening condition a combination of methotrexate and a biologic is recommended for the starting treatment, 3) superiority of other TNF-α inhibitors over etanercept in chronic anterior uveitis (etanercept in ineffective in ocular inflammatory diseases), 4) TNF-α inhibitors dose should be boosted and/or interval should be shortened in inadequate response to standard dose of TNF-α inhibitors, 5) second TNF-α inhibitor should be employed after failing the first one, 6) abatacept and tocilizumab can be employed in patients who fail methotrexate and two TNF-α inhibitors, and 7) all effective medications should be continued for 2 years before tapering therapy.

References

Maleki A, Anesi SD, Look-Why S, Manhapra A, Foster CS. Pediatric uveitis: A comprehensive review. Surv Ophthalmol. 2022;67(2):510-529.

 

A new landmark publication by leading international experts in uveitis and glaucoma – the Uveitic Glaucoma Interest Group (UGIG). In this publication, the UGIG outlines updated treatment and follow-up recommendations for the management of Uveitic Glaucoma, including a stricter intraocular pressure (IOP) target of 16 mmHg to better protect vision.

Please check out the attached flyer which summarizes these new recommendations on Uveitic Glaucoma! If you’d like to learn more, please visit https://uveiticglaucoma.com/ where you can listen to an AI-generated podcast summary of the article, find a link to the publication, and download the flyer.

Birdshot Retinochoroidopathy

C. Stephen Foster, MD, FACS, FACR

What is Birdshot Retinochoroidopathy?

Birdshot retinochoroidopathy, commonly referred to simply as “birdshot”, is a rare form of posterior uveitis which mainly affects the retina and choroid. The disease occurs in women more often than men, typically Caucasian, and most often between the ages of 30 and 60. “Birdshot” can be a severe and blinding disease if unrecognized or undertreated.

What causes “birdshot”?

The etiology of the disease is, as yet, unknown. There is a class of genes known as human leukocyte antigens (HLA), and specifically one called HLA-A29 (also HLA-A29.2 or HLA-A*2902), that is present in the overwhelming majority of “birdshot” patients, and is thought to be involved in the development of the disease. Infection, by virus or bacteria, in susceptible individuals is thought to act as a trigger, with the disease then being self-propagated by an autoimmune mechanism.

What are the symptoms of “birdshot”?

It is normally a chronic problem, with symptoms that develop and progressively worsen over several months to years. The most common complaints are:

• Floaters and flashes
• Blurry or hazy vision, sometimes described as looking through murky water
• Decreased color and/or night vision

Patients usually do not complain of pain or redness, though it can be present. There are not any systemic diseases that are typically associated with “birdshot”.

How do you diagnose “birdshot”?

Clinical examination is the most important tool in the diagnosis of “birdshot”, though a full history and review of systems must be performed to help evaluate for other potential infectious or autoimmune causes. Examination often shows little to no inflammation in the “front” of the eye, however dilated exam can reveal a dense collection of inflammatory cells and debris in the vitreous, pallor of the optic nerve, attenuation of retinal vessels, retinal vasculitis, macular edema, and the presence of “birdshot lesions” or creamy yellow-white spots involving the retina and choroid. Cataract formation can also occur as a result of long-standing inflammation or chronic use of corticosteroid eye drops. Rarely, new blood vessels can sometimes grow between choroid and retina which can cause severe vision loss even after inflammation is treated.

What testing is performed to help diagnose “birdshot”?

A large array of clinical testing can be very helpful, starting with checking blood work, especially for the presence of the HLA-A29 gene when “birdshot” is suspected. Color vision testing can show mild to severe deficit. Fundus autofluorescence may reveal abnormal areas of hypopigmentation that correspond to “birdshot lesions” or overlap areas or normal appearing retina. Fluorescein angiography may show window defects in areas of “birdshot lesions” or evidence of macular edema, retinal vasculitis, optic nerve inflammation, or choroidal neovascularization. Indocyanine green (ICG) angiography is used to evaluate the choroid, and can show hypolucent lesions that may not be visible on dilated exam. Visual field testing with a blue-on-yellow protocol (shortwave automated perimetry, or SWAP) is more sensitive than normal white-on-white visual field testing, and may show more advanced field defects. Optical coherence tomography (OCT) can reveal macular edema or epiretinal membranes. Lastly, and perhaps most importantly, standard electroretinogram (ERG) can be a very useful tool in both the diagnosis of “birdshot”, and in assessing response to therapy, particularly the 30-Hertz photopic protocol, which will often show delayed implicit times and decreased signal amplitudes that may improve with treatment.

Can “birdshot” be treated?

Yes, this disease is very treatable, and after proper treatment, it is even possible to achieve long-term remission of active inflammation while off all medications. Unfortunately, damage done to retina and choroid, and to most other parts of the eye affected, is irreversible, which makes timely recognition and initiation of therapy the key to a good outcome and preserving vision.

How do you treat inflammation from “birdshot”?

“Birdshot” is a severe and stubborn form of uveitis, and as with all types of uveitis, inflammation must be quieted by whatever means necessary or blindness will ensue.

Corticosteroids
Coritosteroids are usually the way to treat most non-infectious uveitis quickly, but for “birdshot”, the way in which they are given may have an effect on the disease course. Our research at MERSI has found that patients who have received oral corticosteroids have shown a higher rate of disease recurrence, even after achieving long-term remission on immunomodulatory therapy. Injection into the eye (intravitreal injection) was not shown to have this risk. Topical eye drops are not effective in treating inflammation in the back of the eye.

Immunomodulatory Therapy
Immunomodulatory therapyis the standard of care for treating birdshot retinochoroidopathy. Our years of experience at MERSI treating patients with “birdshot” have shown the most effective initial treatment strategy involves starting combination therapy with mycophenolate mofetil (CellCept®), an antimetabolite, and modified cyclosporine A, a calcineurin-inhibitor. In cases of intolerance or poor efficacy, mycophenolate is sometimes replaced with another antimetabolite, or the patient is transitioned to intravenous therapy with a TNF-α inhibitor such as infliximab (Remicade®). Stubborn and poorly controlled disease on these medications may require use of an alkylating agent such as cyclophosphamide (Cytoxan®).

Corticosteroid Implant
A corticosteroid implant surgically placed within the eye, fluocinolone (Retisert®), can be used for patients who are not able to achieve remission on or tolerate immunodulatory therapy, or in cases where this option presents less of a burden on life than long-term medical therapy.

What other problems are associated with “birdshot” and how are they treated?

Cataracts and Glaucoma
Cataracts and glaucoma can both occur as a result of active inflammation or long-term treatment with corticosteroids.

• Cataracts can be removed, ideally when inflammation has been treated and the eye is quiet, but may need to be removed to see and treat problems inside the eye.
• Glaucoma is initially treated with eye drops, followed by laser therapy, and lastly surgery if necessary.

 

Retina
Problems with the central retina, especially macular edema and epiretinal membranes, are frequently seen.

• Macular edema may resolve when inflammation is treated, however if it persists, it can also be treated with topical NSAIDs or oral acetazolamide.
• Epiretinal membranes can be surgically removed if they are felt to cause progressively worsening vision. Intraocular injection of either corticosteroid or a VEG-F inhibitor, such as bevacizumab (Avastin®), is extremely effective in treating macular edema. These can also be used to treat choroidal neovascularization, new blood vessels that grow between retina and choroid as a result of a break in the barrier that lies between them.